Open access

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

Written By

Rene Anand, Stephanie A. Amici, Gerald Ponath, Jordan I. Robson, Muhammad Nasir and Susan B. McKay

Submitted: November 10th, 2010 Published: August 17th, 2011

DOI: 10.5772/20752

Chapter metrics overview

3,251 Chapter Downloads

View Full Metrics

1. Introduction

Autism Spectrum Disorders (ASD) are a set of complex neurodevelopmental disorders defined behaviorally by impaired social interaction, delayed and disordered language, repetitive or stereotypic behavior and a restricted range of interest (Fombonne, 1999). ASD affect nearly 1 in 110 children, and disproportionally affect four times as many boys as girls. Comorbid symptoms often include seizures, sleep problems, gastrointestinal disorders, and metabolic deregulation (Coury, 2010). As such, ASD are an enormous challenge for parents, medical professionals, and educators. Their treatments put a significant financial strain on healthcare systems worldwide. There is no pharmacotherapy proven effective for treating the core deficits in ASD. There is also a paucity of biomarkers for autism. Both genetic and environmental factors are thought to contribute to autism susceptibility (Courchesne, 2007; Geschwind, 2009; Südhof, 2008; Ramocki & Zoghbi, 2008), but because only some of the genetic factors have been identified unequivocally thus far (Cook & Scherer, 2008; Levitt & Campbell, 2009), finding effective treatments that target the underlying causes of ASD remains a major challenge.

Identifying endophenotypes and biomarkers for complex and heterogeneous disorders such as ASD are important not only to elucidate their etiologies, but also to identify suitable biochemical molecules and pathways to target the treatment of core deficits. In this review, we present a rationale that neuronal nicotinic acetylcholine receptor (nAChR) alterations are biomarkers for ASD and that specific nAChRs subtypes are likely to be useful therapeutic targets for the treatment of core deficits. This rationale is based on the synthesis of emerging evidence from multiple types of studies, including our own, using postmortem, genetic, functional, and molecular neurobiological methodologies from two disparate areas of research – autism spectrum disorders and nicotine dependence.

Advertisement

2. Neuronal nicotinic acetylcholine receptors

Neuronal nAChRs are a family of ion channels that are permeable to both monovalent (Na+ and K+) and divalent (Ca++) cations and are formed by assembly of different combinations of subunits termed α2 to α10 and β2 to β4. These channels are heteropentamers with the exception of the α7 nAChR, which is usually a homopentamer (Lindstrom, 1996; Lindstrom, 1997; Sargent, 1993). In neurons, nAChRs regulate the release of many different neurotransmitters including acetylcholine, dopamine, γ-aminobutyric acid (GABA), glutamate, and serotonin at presynaptic sites (McGehee & Role, 1996) and mediate fast synaptic transmission at postsynaptic sites (Zhang et al., 1996; Frazier et al., 1998a; Frazier et al., 1998b). These functions have a broad range of physiological effects on reward, analgesia, anxiety, affect, locomotion, attention, mood, learning, memory, and executive function (Miwa et al., 2011). nAChRs can also modulate neurite growth (Pugh & Berg, 1994; Lipton et al., 1998) and cell survival (Pugh & Margiotto, 2000; Messi et al., 1997; Kihara et al., 1997; 1998; 2001). nAChRs have been intensely studied for many decades not only to understand their normal physiological roles, but more importantly to elucidate their pathophysiological role in mediating addiction to nicotine in tobacco, because tobacco use among smokers, in particular, results in greater than 400,000 deaths per year in the U.S. alone. In addition to their role in nicotine addiction, nAChR dysfunctions are also implicated in other disorders, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, attention deficit-hyperactivity disorder, anxiety disorders, Tourette’s syndrome, and depression (Newhouse & Kelton, 2000; Newhouse et al., 2004; Mineur & Picciotto, 2010).

Advertisement

3. Alterations of nAChRs in ASD

3.1. Changes in α4β2 nAChR expression

Examination of postmortem brains of individuals with ASD has identified major nAChR abnormalities in multiple postmortem studies. In the first such study to be undertaken, postmortem tissue from 7 adults with a mean age of 24 years was examined. High-affinity 3[H]epibatidine binding was reported to be significantly reduced in the frontal and parietal cortex of these individuals with ASD compared to age-matched controls. Furthermore, immunohistochemical analyses showed that the loss of 3[H]epibatidine correlated with reduced expression of the α4 and β2 nAChR subunits. Notably, the mRNA for these two nAChR subunits was not significantly decreased, suggesting that the reduction in nAChR subunit levels resulted from an impaired posttranslational mechanism. Also, 3[H]pirenzepine binding to M1 and M2 muscarinic AChRs (mAChRs) was not significantly altered, suggesting that the loss of nAChR expression resulted from deregulation of a posttranslational mechanism that specifically affected nAChRs, but not mAChRs (Perry et al., 2001). In a subsequent study, postmortem tissue from 8 adults with a mean age of 24 years was examined. Again, high-affinity [3H]epibatidine binding was reported to be significantly reduced by greater than 50% in the cerebellar cortex of individuals with ASD. High-resolution analyses of the autoradiographic data indicated that the loss of 3[H]epibatidine binding occurred in the granule cell layer, the Purkinje layer, and the molecular cell layer of the cerebellum of individuals with ASD compared to age-matched controls. Significant reduction in the expression of the α4 nAChR subunit, but not its mRNA (Lee et al., 2002), was also observed and is consistent with the notion that α4β2 nAChR loss results from an impaired posttranslational mechanism regulating it expression. In a third study, immunohistochemical analysis of postmortem brains from 3 adults with ASD of mean age 29 years surprisingly showed no changes in the expression of the α4 nAChR subunit in the thalamus compared to age-matched controls. However, reduction of the β2 nAChR subunit was observed in the paraventricular nucleus and nucleus reuniens of the thalamus (Martin-Ruiz et al., 2004).

3.2. Changes in α7 nAChR expression

In contrast to the loss of 3[H]epibatidine binding and decreased expression of the α4 and β2 nAChR subunits, no significant change in the binding of 125I-α-bungarotoxin to the α7 nAChR or immunohistological detection of the α7 nAChR (Perry et al., 2001) was reported in the frontal and parietal cortex. In the cerebellar cortex, however, binding of α-bungarotoxin to the α7 nAChR and immunohistological detection of the α7 nAChR did show a significant increase in the expression of the α7 nAChR in the granule cell layer, but not in the Purkinje cells or the molecular cell layer. Interestingly, similar to the β2 nAChR subunit, reduction of the α7 nAChR subunit was also observed in the paraventricular nucleus and nucleus reuniens of the thalamus. Thus, alterations in the expression of both the α4β2 nAChR and the α7 nAChR in individuals with ASD appears to show regional specificity (Perry et al., 2001; Lee et al., 2002; Martin-Ruiz et al., 2004), suggesting that these changes are compensatory and result from altered homeostasis of neural networks, rather than the direct effect of a single molecule in a particular molecular pathway.

Two recent studies on rare genomic microdeletions and copy-number variations (CNVs) revealed a possible involvement of the CHRNA7 gene in some cases of autism. The first study investigated segmental duplications at breakpoints (BP4–BP5) of chromosome 15q13.2q13.3 from 1441 individuals with autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository (Miller et al, 2009). This genomic sequence spans over 1.5 Mb and includes CHRNA7. From this cohort 10 patients were identified with genomic imbalance at chromosome 15q13.2q13.3, including five with BP4–BP5 microdeletions. Among the 1420 parents and 132 unaffected/unknown siblings no cases of BP4–BP5 microdeletion were found. The second study on genomic CNVs explored the genetic contribution to ASD in a large cohort of families (Simons Simplex Collection consisting of 915 families) with a single autistic child and at least one unaffected sibling (Levy et al., 2011). The contribution of the transmission of ‘‘ultrarare’’ variants to ASD, in particular inherited genomic duplications was also estimated. A transmitted duplication within the CHRNA7 gene was observed in 8 autistic children and 3 unaffected siblings within 6 families. A further network-based analysis of genetic associations (NETBAG) of that dataset strengthened the involvement of CHRNA7 as one of the genes affected by rare de novo CNVs in autism (Gilman et al., 2011).

Advertisement

4. nAChRs modulate multiple behaviors deficient in ASD

ASD is defined by three behavioral deficits, impaired social interactions, repetitive behaviors, and delayed language. Multiple studies using animal models implicate a functional role for nAChRs in some of these behavioral deficits in ASD. β2-containing nAChRs regulate executive and social behaviors in studies using β2 nAChR subunit knockout mice (Granon et al., 2003). Knockout β2 nAChR mice show a decrease in slow exploratory behavior - a measure of cognitive function during which animals slowly and precisely explore their environment, a lack of sensitization to novel stimuli, and abnormal social behavior during aggressive confrontations with other mice (Granon et al., 2003). Recovery of the slow exploratory behavior was observed by injecting a lentiviral vector expressing the β2 nAChR subunit into the ventral tegmental area (VTA) in the knockout mice (Maskos et al., 2005). Re-expressing the β2 nAChR subunit in the prefrontal cortex also improves social abnormalities in this knockout mouse. Increased social interaction and decreased novel exploration in a social interaction paradigm with concurrent motivation was ameliorated after stereotaxically injecting the β2 nAChR subunit into the prelimbic area of the prefrontal cortex (PFC) (Avale et al., 2011).

As previously mentioned, nAChR dysfunction is also implicated in several other neurological disorders with repetitive behavior. We suggest here that similarities in behaviors across those neurological conditions, as well as high prevalence of simultaneity suggest a possible shared underlying mechanism. Moreover, there has been a recent push to redefine repetitive behavior in these neuropsychiatric disorders and instead characterize stereotypies into disorder-related endophenotypes rather than separate disorder-specific symptoms (Kas et al., 2007, Langen et al., 2011). Tourette’s syndrome (TS), obsessive compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD), all involve disordered cortical-basal ganglia circuitry and all can be successfully treated with drugs acting on nAChRs. The basal ganglia and orbitofrontal cortex, both regions highly innervated by nicotinic acetylcholine receptor rich interneurons are hyperactive during PET/SPECT studies of OCD (Baxter et al., 1988) and hypoactive in studies of ADHD (Zametkin et al., 1990) and TS (Braun et al., 1995). The orbitofrontal cortex controls inhibition and disinhibition of behavior, and lesions in this area are sufficient to cause impulsive and inappropriate behavior. Nicotine or an analog alone has demonstrated potential to treat repetitive behaviors in these disorders. A transdermal nicotine patch, administered as therapy for TS, decreases the severity and frequency of tics, a compulsory symptom of TS (Sanberg, 1997). Nicotine gum administered to OCD patients previously resistant to other treatment clinically improved behavior (Carlsson, 2001; Pasquini et al., 2005). Interestingly, clomipramine, an SSRI commonly prescribed for the treatment of OCD, also acts on nAChRs (Lopez-Valdes, 2002). Lastly, (-)-Nicotine and ABT-418, an α4β2 nAChR agonist (Potter et al., 1999), both successfully treat adults with ADHD (Levin and Simon, 1998; Wilens et al., 1999). It is interesting to note that hyperactivity, tics, and obsessive compulsive disorder are all common comorbid disorders seen in patients with ASD with approximately 59% of ASD patients having impulsivity problems, 8-10% having tics, and 37% having OCD (Levy et al., 2009). Although it is clear that similar neurocircuitry is involved in several disorders with repetitive behavior, further research is needed to determine whether the underlying mechanisms causing this dysfunction overlap in TS, OCD, ADHD, and in ASD.

nAChRs also are involved in several other non-core, but frequently occurring symptoms in ASD. The most common comorbid disorders and symptoms associated with ASD are psychiatric (e.g., depression and anxiety), neurological (e.g., epilepsy), sleep, and sensory (e.g., tactile) disorders. Epilepsy occurs in 5-49% of people with autism (Levy et al., 2009). Genetic abnormalities in CHRN4A and CHRNB2, encoding the α and β nAChR subunits respectively, are sufficient to cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (De Fusco, 2000; Bertrand, 2002; Steinlein, 2002; Hoda, 2009), however ADNFLE is not associated with ASD. 52-73% of patients with ASD experience sleep disruption and 43-84% experience anxiety disorders. Knocking out the α4 nAChR subunit increases anxiety in mice (Ross et al., 2000) and the β2 nAChR knockout animal shows abnormal sleep pattern (Lena et al., 2004). These studies demonstrate that behaviors regulated by nAChRs are disparate and commonly aberrant in ASD and suggest the potential for nAChR-acting drugs in the treatment of ASD.

Lastly, there is accumulating evidence that the immune system is disrupted in individuals with ASD (Careaga et al., 2010). Elevated levels of chemokines have been detected in the brains and cerebrospinal fluid (Chez et al., 2007; Wills et al., 2009) as well as the plasma (Ashwood et al., 2011a) of individuals with ASD, and this elevation correlated with more impaired behavior (Ashwood et al., 2011b). Furthermore, postmortem studies of individuals with autism also detected presence of activated neuroglial cells in their brain (Vargas et al., 2005). In a recent study, activated microglia were detected in the dorsolateral PFC in 5 out of 13 samples, 2 of which were under the ages of 6 years (Morgan et al., 2010). These results suggest that inflammation of the central nervous system, at least in some individuals, may contribute to the neuropathology of ASD. Thus, suppression of neuroinflammation by targeting α7 nAChRs in ASD may be potentially beneficial.

Advertisement

5. Neurexin and neuroligin deficits in ASD

The neurexins are cell adhesion molecules encoded by three genes corresponding to neurexins 1, 2 and 3 (Missler & Südhof, 1998; Lise & El-Husseini, 2006). As a result of transcriptional initiation from two different promoters, each neurexin gene encodes a longer α-neurexin protein and a shorter β-neurexin protein. The proteins are identical from their intracellular C-termini through their transmembrane domains, glycosylation-rich domains and the sixth LNS domain of α-neurexin, which corresponds to the only LNS domain in β-neurexin. They have divergent N-terminal extracellular domains, which allow for interactions with multiple proteins. Additionally, alternative splicing at multiple splice sites within each gene can give rise to more than one thousand different isoforms, which differ only in their extracellular domains. Neurexins recruit N- and P/Q-type calcium channels to active zones of presynaptic terminals through scaffolding proteins, including calmodulin-associated serine/threonine kinase (CASK) (Hata et al., 1996; Missler et al., 2003; Zhang et al., 2005). α-neurexins were reported to specifically induce GABAergic postsynaptic differentiation (Kang et al., 2008). The enormous structural diversity of the neurexins suggests that they are involved in a multitude of physiological functions yet to be elucidated.

Results from a linkage and copy number variation analysis conducted by the Autism Genome Project Consortium (Szatmari et al., 2007) show that neurexin-1 dysfunction is associated with ASD. This conclusion has been corroborated in multiple linkage analysis studies since (Kim et al., 2008; Marshall et al., 2008) and in analysis of structural variants in the α- and β-neurexin genes (Zahir et al., 2008; Feng et al., 2006; Yan et al., 2008; Gai et al., 2011; Gauthier et al., 2011). Neurexin knock-out animals have provided insights into the functions of the neurexin family. Neurexin 1/2/3α- triple knock-out animals die perinatally and have reduced spontaneous and evoked neurotransmission at glutamatergic and GABAergic synapses, demonstrating that α-neurexins are necessary for neurotransmitter release at synapses (Missler et al., 2003). Additionally, mice lacking neurexins have impaired neuroendocrine secretion (Dudanova et al., 2006), which may mirror some children with autism that exhibit dysfunction of the hypothalamic-pituitary-adrenocortical system, possibly due to altered neuroendocrine regulation (Corbett et al., 2006). Similar to the neurexin triple knockout animals, mice lacking neurexin1/2α or neurexin2/3α die within 1 month after birth and have reduced neurotransmission. Analyses of brain morphology in α-neurexin knockouts revealed no major impairments in synapse formation, but minor reductions in dendrite branch length and spine numbers were detected, suggesting they are important in synapse maturation more so than formation (Dudanova et al., 2007). None of the single α-neurexin knock-out animals have dramatic phenotypes, with the neurexin-2α knock-out animals showing the least severe phenotype (Craig & Kang, 2007). In the absence of neurexin-1α, miniature excitatory postsynaptic currents were reduced in recordings from hippocampal slices. Behaviorally, the neurexin-1α−deficient mice were identical to wild-type mice in multiple social interactions, but displayed decreased grooming behavior, impaired nest building, decreased pre-pulse inhibition, and improved motor learning in behavioral studies (Etherton et al., 2009). While the neurexin-1α−deficient mice display behavioral phenotypes similar to what is seen in autism they are not sufficient to explain ASD yet they still provide a useful but limited model of ASD. The β-neurexin and combined α- and β-neurexin knockout animals have not yet been fully evaluated.

The neuroligins are encoded by five differentially spliced genes that encode multiple neuroligin isoforms (Zhang et al., 2005; Boucard et al., 2005). In complementary roles, neuroligins, the postsynaptic binding partners of neurexins, recruit N-methyl-D-aspartate (NMDA) receptors and GABAA receptors through their interactions with scaffolding proteins such as post-synaptic density 95 (PSD-95) and gephyrin, respectively (Graf et al., 2004; Nam & Chen, 2005; Chih et al., 2006; Poulopoulos et al., 2009). Thus, bi-directional interactions between neurexins and neuroligins appear to serve a critical function in the assembly and maturation of both glutamatergic and GABAergic synapses through recruitment of the requisite presynaptic and postsynaptic components of neurons (Dean & Dreshbach, 2006; Craig & Kang, 2007; Sudhof, 2008).

Neuroligins are strongly implicated in ASD. Chromosomal rearrangements and copy number variations in neuroligin-1 are linked to autism (Konstantareas & Homatidis, 1999; Ylisaukko-oja et al., 2005; Glessner et al., 2009). There is also evidence that mutations in neuroligin-3 and neuroligin-4 are found in patients with ASD (Laumonnier et al., 2004; Jamain et al., 2003). In addition mouse models support a role for neuroligins in ASD. Neuroligin-1 knock-out mice are viable and fertile, but also have synaptic dysfunctions (Chubykin et al., 2007). At the molecular level, the NMDA/AMPA ratio at corticostriatal synapses is reduced, which is associated with repetitive grooming that may mirror some of the repetitive behaviors seen in autistic patients (Blundell et al., 2010). In contrast to neuroligin-1-deficient mice, which show impaired NMDA receptor signaling, neuroligin-2 knock-out animals have deficits in inhibitory synaptic transmission (Chubykin et al., 2007). Behaviorally, neuroligin-2 knock-out mice exhibit increased anxiety, but normal social interactions (Blundell et al., 2009), similar to the neurexin-1α-deficient mice. Mutations in neuroligin-3 and neuroligin-4 lead to intracellular retention of the mutant proteins (Chih et al., 2004; Comoletti et al., 2004). The neuroligin-3 R451C mutation is a gain of function mutation. Mice with this point mutation exhibited impaired social interactions and increased inhibitory synaptic transmission (Tabuchi et al., 2007). Mice lacking neuroligin-4 correspond to loss-of-function mutations in human neuroligin-4 and show deficits in reciprocal social interactions and ultrasonic communication (Jamain et al., 2008). Neuroligin 1/2/3α triple knock-out animals die at birth, but similar to their α-neurexin-deficient counterparts, do not show dramatic reductions in synapse numbers or brain architecture, but do have severely impaired synaptic transmission (Varoqueaux et al., 2006).

The studies of the neurexin and neuroligin functions indicate a role for them in proper synaptic function but not synapse formation. Although it is clear that the deficits of neurexins and neuroligins play a role in ASD, understanding their interactions with receptors will provide additional insight into their functions.

Advertisement

6. Neurexins associate with multiple receptors, including nAChRs

Accumulating evidence indicates that neurexins interact directly with more than the neuroligins. Our laboratory was the first to provide experimental evidence for direct interactions between neurexins and receptors by showing that neurexin-1β coimmunoprecipitates with recombinant α4β2 nAChRs when expressed in heterologous cells (Cheng et al., 2009). Functionally, the neurexin-1β regulates targeting of α4β2 nAChRs to pre-synaptic terminals in neurons (Cheng et al., 2009). Complementary studies report a role for neurexin-1 and neuroligin-1 in recruitment of α3-containing nAChRs to the post-synaptic density (Conroy et al., 2007; Ross & Conroy, 2008). In addition, recent studies show that neurexins interact with multiple receptors. First, neurexin-1β interacts with GABAA receptors; this interaction modulates the cell surface expression levels of the GABAA receptors but not its functions per se (Zhang et al., 2010). Second, leucine-rich repeat transmembrane protein (LRRTM2) binds trans-synaptically to both neurexin-1α and-1β and induces presynaptic differentiation at excitatory synapses (Ko et al., 2009; de Wit et al., 2009; Siddiqui et al., 2010). Knock-down of LRRTM2 in the rat dentate gyrus shows a large reduction in AMPAR-mediated EPSCs in in vivo recordings from granule cells in hippocampal slices. Furthermore, the association between neurexin-1 and LRRTM2 is a functional interaction. When neurexin-1 is knocked-down in hippocampal neurons, LRRTM2 is unable to induce presynaptic differentiation (de Wit et al., 2009). Finally, neurexins associate with GluRδ2 receptors via a soluble protein called cerebellin -1 precursor protein (Cbln1) (Uemura et al., 2010). In the Cbln1 knockout mice, the synaptogenic activity of GluRδ2 receptor is lost. Thus, GluRδ2 mediates cerebellar synapse formation by interacting with presynaptic neurexins via Cbln1.

Advertisement

7. Genetic variants of neurexin-1 are linked to nicotine dependence

A recent high-density genome-wide association study for nicotine dependence linked single nucleotide polymorphisms (SNP) in the neurexin-1 gene to the development of nicotine dependence and thus smoking behavior (Bierut et al., 2007). A second independent study also showed linkage between a variant of the neurexin-1 gene and nicotine dependence in smokers of European and African-American ancestry (Nussbaum et al., 2008). These results, along with the fact that neurexins functionally target α4β2 nAChRs to synapses, implicate neurexins in the etiology of other neurological diseases typically associated with pathophysiological functions of nAChRs. α4β2 nAChRs mediate essential features of nicotine addiction including reward, tolerance, and sensitization (Tapper et al., 2004). Thus, functions are likely to be affected by changes in the expression levels of neurexin-1. The exact mechanism by which neurexin-1α and -1β splicing is regulated to generate the predicted hundreds of neurexin-1 isoforms remains to be elucidated. It is possible that a regulatory SNP in the intron of the neurexin-1 gene could modulate neurexin-1 expression or splicing efficiency and thus influence nAChR functions by regulating their synaptic targeting efficiency. Because there are hundreds of neurexin-1α isoforms, the linkage between neurexin-1 gene variants, α4β2 nAChR synaptic targeting, and nicotine dependence requires additional studies. Nevertheless, the functional linkage between neurexin-1 and α4β2 nAChR and their converging roles in nicotine dependence suggests that α4β2 nAChR activity may regulate neurexin-1 gene expression.

Advertisement

8. nAChR modulate excitation-inhibition balance

There is strong evidence that some forms of ASD are caused by an imbalance of excitatory and inhibitory synaptic transmission in neuronal circuits that are responsible for the establishment of language processing and social behavior during prenatal and postnatal brain development. Increased glutamatergic (excitatory) signaling or suppressed GABAergic (inhibitory) signaling is sufficient to disrupt the excitatory/inhibitory balance in local circuit-plasticity (Rubenstein & Merzenich, 2003). A hyperexcitable cortex is poorly differentiated functionally and therefore inherently unstable and susceptible to epilepsy. This might explain why, in addition to the autistic core symptoms, an average of ~30% of individuals with ASD develop clinically apparent seizures (Gillberg & Billstedt, 2000). In several mouse models of autism this lack of homeostasis of excitatory and inhibitory signaling was observed (Tabuchi et al., 2007; Gogolla et al., 2009). In the frontal cortex, cholinergic transmission can modulate cortical tone establishing a homeostasis of excitatory and inhibitory signals (Aracri et al., 2010). In layer V of the prefrontal cortex, nAChR activation increases the threshold for activating glutamatergic synapses (Couey et al., 2007), whereas GABA release is stimulated in several cortical layers by nAChR activation (Alkondon et al., 2000).

We posit that some of the regulatory effects of balancing inhibitory and excitatory synaptic transmission are mediated by synaptic targeting of nAChRs by neurexins. This results in the change of expression levels of nAChRs in various brain regions of autistic individuals. Therefore allosteric modulators or direct agonists targeting nAChRs by might be useful to restore the imbalance of excitatory and inhibitory synaptic transmission caused by deregulated expression of neurexin-1.

Advertisement

9. Nicotinic receptors as biomarkers for ASD

9.1. Positron Emission Tomography ligands for α4β2 nAChRs

The alterations in nAChRs in ASD may also serve as an early molecular biomarker, detectable by imaging tools such as positron emission tomography (PET), the most advanced modality for non-invasive study of receptors. Monitoring the reversal of the loss of α4β2 nAChR in the frontal, parietal, and cerebellar cortex and the upregulation of α7 nAChR in the cerebellar cortex by PET imaging in the brains of individuals with ASD might provide a clinical tool to complement behavioral tests needed to assess the effectiveness of novel pharmacotherapies for autism.

Three radiotracers, [11C]nicotine, (S)-3- (azetidin-2-ylmethoxy)-2-[18F]fluoropyridine (2-[18F]FA) and (S)-5- (azetidin-2-ylmethoxy)-2-[18F]fluoropyridine (6-[18F]FA), have been used for studying α4β2 nAChRs in the human brain using PET. The PET imaging properties of these radioligands are not perfect however. Poor signal-to-noise ratios and other drawbacks of [11C]nicotine suggest that this radiotracer is not well suited for quantitative imaging in animals and humans. 2-[18F]FA is the only currently available radioligand for quantitative imaging nAChR in humans. The “slow” brain kinetics of 2-[18F]FA and 6-[18F]FA hamper mathematical modeling and reliable kinetic parameter estimation since it takes many hours of PET scanning (5–7 h) for the tracer radioactivity to reach a spatial-temporal steady state (Horti et al., 2010). Another crucial problem with 2-[18F]FA and 6-[18F]FA is relatively low binding potential (BP) in extrathalamic regions (BP ≤ 0.6–0.8), including the cortex, which has a lower nAChR density. Altered densities of cortical and striatal nAChRs in neurodegenerative diseases (Pimlott et al., 2004) and schizophrenia (Ochoa & Lasalde-Dominicci, 2007) illustrates the importance of imaging extrathalamic nAChRs.

A variety of radioligands with fast regional brain kinetics have been presented in non-human primates and pigs. Analogs of epibatidine showed “rapid” brain kinetics and improved BP (Gao et al., 2007, 2008). One compound of the series, (-)-2-(6-[18F]fluoro-2,3'- bipyridin-5'-yl)-7-methyl-7-aza-bicyclo[2.2.1]heptane ([18F]JHU87522 or [18F]AZAN) exhibited better imaging properties in animal studies than those of 2[18F]FA and 6-[18F]FA including a greater BP value and faster brain kinetics. In addition, the brain uptake of [18F]AZAN is greater and its acute toxicity is lower. Most available PET and single photon emission computed tomography (SPECT) imaging agents for nAChR are agonists and these nAChR-agonists are toxic when injected at high doses. Unlike 2-FA that is nAChR agonist, AZAN displays properties of functional antagonist of α4β2 nAChR. Currently, AZAN is undergoing toxicological studies that will determine if this radioligand is sufficiently safe for clinical application as a PET radiotracer. If [18F]AZAN is safe for human PET studies, there are strong indications that it could become the radiotracer of choice for PET imaging of nAChR in human brain (Horti et al., 2010).

9.2. Positron Emission Tomography ligands for α7 nAChRs

Several radiotracers were developed for selective imaging of the α7 nAChRs in the human brain for PET and SPECT (Dolle et al., 2001; Pomper et al., 2005; Ogawa et al., 2006). Despite these efforts, there have been no clinical studies using these radioligands for α7 nAChRs in the human brain.

Very recently, 4-[11C]methylphenyl 2,5-diazabicy- clo[3.2.2]nonane-2-carboxylate ([11C]CHIBA-1001) was developed as a novel PET ligand for α7 nAChRs in the conscious monkey brain. An in vitro binding study showed that the IC50 value of CHIBA-1001 for [125I]α-bungarotoxin binding to the rat brain homogenates was 45.8 nM. [11C]CHIBA-1001 distribution in the monkey brain measured by PET was consistent with the regional distribution of α7 nAChRs. Moreover, brain uptake of [11C]CHIBA-1001 was dose-dependently blocked by pretreatment with the selective α7 nAChR agonist SSR180711, but was not altered by the selective α4β2 nAChR agonist A-85380 (Hashimoto et al., 2008).

In the human brain, [11C]CHIBA-1001 was found widely distributed in all brain regions. The regional distribution pattern of [11C]CHIBA- 1001 is consistent with what is expected in vitro (Falk et al., 2003; Court et al., 1999; 2001; Marutle et al., 2001), but different from that of α4β2 nAChRs (Clementi, 2004). However, it is slightly different from the regional distribution in the monkey brain (Hashimoto et al., 2008). In the human brain, remarkable radioactivity accumulation was observed in the cerebellum. These findings suggest that [11C]CHIBA-1001 is a suitable radioligand for imaging α7 nAChRs in the human brain, as it offers acceptable dosimetry and pharmacological safety at the dose required for adequate PET imaging (Toyohara et al., 2009).

These recent advances in the development of new nAChR PET radioligands, like [18F]AZAN for α4β2 nAChRs and [11C]CHIBA-1001 for α7 nAChRs with fast kinetics and low toxicity will provide promising tools for monitoring alterations of brain nAChR especially in young patients with ASD. The principal downside to the use of PET is the unknown risk of using radioactive ligands and sedatives, especially in younger individuals, to perform PET scans.

Advertisement

10. Nicotinic drugs as therapeutic agents for ASD

10.1. Agonists

10.1.1. α4β2 nAChRs

The extensive loss of α4β2 nAChRs in some individuals with ASD provide a rationale for exploratory trials of drugs that can upregulate and activate α4β2 nAChRs and thus compensate for their loss both physically and functionally. The panoply of drugs developed over the last few decades for smoking cessation therapy as well as other disorders with pathophysiological roles for nAChRs (Taly et al., 2009), offers a large selection of drugs that are likely to be specific for α4β2 nAChRs and capable of upregulating them. Varenicline (Chantix), one such drug that has FDA approval for use in smoking cessation therapy is a partial agonist of the α4β2 nAChRs (Coe et al; 2005) and of interest for treatment of ASD. Although varenicline is also a full agonist of the α7 AChR (Mihalak et al., 2006), its relative specificity for α4β2 nAChRs is thought to be due to differences in its EC50 for activation of α4β2 nAChRs versus α7 nAChRs, as well as a function of the low concentrations at which it is used clinically for anti-smoking therapy (Niaura et al., 2006). Thus it has become one of the most widely used smoking cessation drugs with millions of users worldwide and shows little sympathetic and parasympathetic complications from cross activation of ganglionic nAChRs (α3β4 nAChRs). Interestingly, much like nicotine, varenicline can upregulate α4β2 nAChRs in vitro. Finally, as a partial agonist, it has the additional benefit of providing chronic low-level activation of α4β2 nAChRs (Papke et al., 2011) and possibly associated downstream intracellular signaling pathways. Varenicline has been shown to change behaviors in some smokers, and a public health advisory from the FDA includes warnings of increased suicidal thoughts and actions. It is important to note, however, that the increase in suicidal thoughts and actions may occur in only a subpopulation of individuals taking varenicline as there is ample evidence that smoking may be more prevalent in those individuals with comorbid neuropsychiatric conditions, including schizophrenia (Adler et al., 1993; Dalack et al., 1999). This may explain behavioral changes reported among smokers using varenicline if individuals have subclinical neuropsychiatric conditions. This idea has been supported by a recent study reporting that there was no clear evidence that varenicline use in itself was associated with an increased risk for depression or suicidal thoughts (Gunnell et al., 2009). Also, unlike in schizophrenia, the prevalence of smoking in individuals with ASD is low (Bejerot & Nylander, 2003), possibly because the loss of α4β2 nAChRs occurs early in development – a clinical feature further strengthening the utility of using α4β2 nAChRs loss as a biomarker for ASD. Nevertheless, any clinical trial of varenicline for individuals with ASD should require close monitoring of possible suicidal ideation given the heterogeneity of causes expected for ASD, some of which may overlap with schizophrenia (Kirov et al., 2009).

10.1.2. α7 nAChRs

It is possible to use α7 nAChR agonists to treat neuroinflammation in ASD. There is strong evidence that activation of the α7 nAChR expressed on monocytes and macrophage, by inhibiting NF-kappaB nuclear translocation, suppresses cytokine release by them (Wang et al., 2003), and that this cholinergic anti-inflammatory pathway that provides a bidirectional link between the nervous and immune system, inhibits the innate immune response (Rosas-Ballina & Tracey, 2009). Hence, a reasonable case can be made for the use of α7 nAChR agonists to treat neuroinflammation in ASD. Individuals could be stratified by monitoring brain inflammation by the uptake of the microglial marker, [11C]PK11195, a PET ligand useful for detecting peripheral benzodiazepine receptors expressed in high amounts in activated microglia (Rojas et al., 2007). However, given that α7 AChR appears to be pathologically upregulated in cerebellum of some individuals with ASD, caution is advocated in the use of α7 AChR agonists to treat ASD. The primary challenge is that the net behavioral benefit from suppressing neuroinflammation mediated by microglia versus over stimulating upregulated α7 AChRs in the granule cell layer, cannot be predicted a priori. Two different α7 nAChR agonists have been used to treat schizophrenia; drugs that might be repurposed for use in individuals with ASD and detectable neuroinflammation.

One of these drugs, GTS-21, or 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist of α7 nAChRs may have beneficial effects in ASD patients. In healthy control subjects, DMXB-A improves attention, working memory, and episodic memory (Kitagawa et al., 2003). The default network, which has been widely reported to be abnormal in schizophrenia (Garrity et al., 2007), is a functionally connected network of brain regions that includes the posterior cingulate cortex, cuneus/precuneus, medial prefrontal cortex, medial temporal lobe, and inferior parietal cortices (Buckner et al., 2008; Tregellas et al, 2011). Altered default network activity has been shown to be a result of DMXB-A administration to patients with schizophrenia (Tregellas et al., 2011), with decreased expression of α7 nAChRs (Freedman et al., 1995).

A second candidate drug, Tropisetron is a partial agonist of the α7 nAChR. Auditory sensory gating P50 deficits are correlated with neuropsychological deficits in attention, one of the principal cognitive disturbances in schizophrenia. In a clinical trial with 33 schizophrenic patients administration of tropisetron, without placebo, significantly improved auditory sensory gating P50 deficits in non-smoking patients with schizophrenia (Shiina et al., 2010). In mice, the early postnatal period represents a critical time window essential for brain development. The administration of tropisetron from postnatal days 2-12 (P2-P12) in mice did not induce significant cognitive, schizophrenia-like or emotional alterations in tropisetron-treated animals as compared to controls, when tested in multiple behavioral assays (Inta et al., 2011).

10.2. Positive allosteric modulators

Galantamine is an acetylcholinesterase inhibitor that also acts as a positive allosteric modulator at the α4β2 and α7 nAChRs (Dajas-Bailador et al., 2003; Samochocki et al., 2003; Schilström et al., 2007). In two studies with small numbers of subjects it has been reported that galantamine showed potential benefits for attention, memory, and psychomotor speed in schizophrenia (Schubert et al., 2006; Lee et al., 2007). An unpublished study from Johnson and Johnson failed to find an advantage for galantamine on a measure of global cognition (clinicaltrials.gov, trial number: NCT 00077727). In a 12-week open-label trial of galantamine, thirteen children with autism, previously unmedicated, (mean age, 8.8 +/- 3.5 years) showed a significant reduction in parent-rated irritability and social withdrawal on the Aberrant Behavior Checklist (ABC), as well as significant improvements in emotional lability and inattention on the Conners' Parent Rating Scale—Revised (Nicolson et al., 2006). Similarly, clinical ratings showed reductions in the anger subscale of the Children's Psychiatric Rating Scale. Eight of 13 participants were rated as responders on the basis of their improvement scores on the Clinical Global Impressions scale. The allosteric properties of galantamine could directly lead to increased release of acetylcholine and activation of postsynaptic nAChRs (Samochocki et al., 2003) or act indirectly through its effects on the release of other neurotransmitters, especially glutamate and dopamine (Schilström et al., 2007; Wang et al., 2007).

It has been demonstrated that amyloid-β precursor protein (APP) is upregulated in a mouse model for Fragile X mental retardation (FXS) (Westmark et al., 2008) and two clinical studies have reported higher levels of APP in children with autism. In the first study, affected children expressed sAPP at 2 or more times the levels of children without autism and up to 4 times more than children with mild autism (Sokol et al., 2006). In the second study, elevated plasma sAPPα was found in 60% of known autistic children (n = 25) compared to healthy age-matched controls (Bailey et al., 2008). Recent studies showed that galantamine allosterically modulates microglial nAChRs and increases microglial beta-amyloid (Aβ) phagocytosis (Wang et al., 2007; Takata et al., 2010).

Collectively, these studies suggest that positive allosteric modulators of α4β2 nAChRs, when used by themselves or in conjunction with agonists, may be beneficial in correcting deficits in the functions of α4β2 nAChRs and thereby core deficits of ASD.

11. Conclusions

This review presents a reasonable rationale based on synthesis of the literature that nAChRs are suitable biomarkers as well as therapeutic targets for addressing core deficits in ASD. Multiple lines of evidence show that nAChRs can modulate many of the functions deficient in individuals with ASD. Furthermore, neuropathological findings, albeit small in numbers, show significant alterations in both α4β2 nAChRs and α7 nAChRs. In the cerebellum, an anatomical area contributing significantly to the etiology of ASD, α4β2 nAChRs are deficient, and α7 nAChRs are upregulated. These findings suggest that well developed PET ligands for both these nAChR subtypes can be used to monitor changes in their expression in response to treatment, behavioral or pharmacological. A novel functional linkage between neurexin-1 and α4β2 nAChR and their converging roles in nicotine dependence suggests that α4β2 nAChR activity may regulate neurexin-1 gene expression. Additionally, agonists and positive allosteric modulators of the α4β2 AChRs are likely to be therapeutic agents that can help restore α4β2 nAChRs expression levels in the brains of individuals with ASD, based on known effects of these agents. A case can be made for the use of α7 nAChRs to reduce neuroinflammation in the brain in those ASD individuals with such clinical pathology. The ultimate hope is that these agents, when administered early in development, by their presumed ability to modulate a number of different neurotransmitter systems and associated signaling pathways, could help correct core deficits associated with ASD.

Acknowledgments

R. A. was a recipient of an Essel Independent Investigator Award from the National Alliance for Research on Schizophrenia and Depression. S. A. A. is a recipient of a Ruth Kirschstein National Research Service Award from the National Institute of Drug Abuse. Support from the National Institutes of Health (NIDA and NIGMS), Autism Speaks, the Ohio State University College of Medicine Medical Research Fund, the Marci and Bill Ingram Comprehensive Center for Autism Spectrum Disorders, and the Gertz family to R. A. is gratefully acknowledged. Thanks to Dr. Eugene Arnold at the OSU Nisonger Center for providing a clinical perspective on ASD. Thanks to Dr. Gregg Wells for editorial comments. Thanks to all the families affected by ASD whose tireless dedication to raising awareness, advocacy and research funds through the annual Columbus Walk Now for Autism Speaks inspire and support the authors’ efforts in ASD research.

References

  1. 1. Adler, L. E., Hoffer, L. D., Wiser, A. & Freedman, R. (1993). Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry 150 1856 1861
  2. 2. Alkondon M. Pereira E. F. Eisenberg H. M. Albuquerque E. X. 2000Nicotinic receptor activation in human cerebral cortical interneurons: a mechanism for inhibition and disinhibition of neuronal networks. J Neurosci 20 66 75
  3. 3. Aracri P. Consonni S. Morini R. Perrella M. Rodighiero S. Amadeo A. Becchetti A. 2010Tonic modulation of GABA release by nicotinic acetylcholine receptors in layer V of the murine prefrontal cortex. Cereb Cortex 20 7 1539 55
  4. 4. Ashwood P. Krakowiak P. Hertz-Picciotto I. Hansen R. Pessah I. N. Van de Water J. 2011aAssociations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. J Neuroimmunol 232(1-2):196-9.
  5. 5. Ashwood P. Krakowiak P. Hertz-Picciotto I. Hansen R. Pessah I. Van de Water J. 2011bElevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun 25 1 40 5
  6. 6. Avale M. E. Chabout J. Pons S. Serreau P. De Chaumont F. Olivo-Marin J. C. Bourgeois J. P. Maskos U. Changeux J. P. Granon S. 2011Prefrontal nicotinic receptors control novel social interaction between mice. FASEB J Mar 18. [Epub ahead of print]
  7. 7. Bailey A. R. Giunta B. N. Obregon D. et al. 2008Peripheral biomarkers in autism: secreted amyloid precursor protein-alpha as a probable key player in early diagnosis. Int J Clin Exp Med 1 338 344
  8. 8. Baxter L. R. Jr Schwartz J. M. Mazziotta J. C. Phelps M. E. Pahl J. J. Guze B. H. Fairbanks L. 1988Cerebral glucose metabolic rates in nondepressed patients with obsessive-compulsive disorder. Am J Psychiatry 145 12 1560 3
  9. 9. Bejerot S. Nylander L. 2003Low prevalence of smoking in patients with autism spectrum disorders. Psychiatry Res 119(1-2):177 EOF 82 EOF
  10. 10. Bencherif M. Lippiello P. M. Lucas R. Marrero M. B. 2011Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell Mol Life Sci 68 6 931 49
  11. 11. Bertrand D. Picard F. Le Hellard S. Weiland S. Favre I. Phillips H. Bertrand S. Berkovic S. F. Malafosse A. Mulley J. 2002How mutations in the nAChRs can cause ADNFLE epilepsy. Epilepsia 43 Suppl 5 112 22
  12. 12. Bierut L. J. Madden P. A. Breslau N. Johnson E. O. Hatsukami D. Pomerleau O. F. Swan G. E. Rutter J. Bertelsen S. Fox L. Fugman D. Goate A. M. Hinrichs A. L. Konvicka K. Martin N. G. Montgomery G. W. Saccone N. L. Saccone S. F. Wang J. C. Chase G. A. Rice J. P. Ballinger D. G. 2007Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet 16 1 24 35
  13. 13. Blundell J. Tabuchi K. Bolliger M. F. Blaiss C. A. Brose N. Liu X. Südhof T. C. Powell C. M. 2009Increased anxiety-like behavior in mice lacking the inhibitory synapse cell adhesion molecule neuroligin 2. Genes Brain Behav 8 1 114 26
  14. 14. Blundell, J., Blaiss, C. A., Etherton, M. R., Espinosa, F., Tabuchi, K., Walz, C., Bolliger, M. F., Südhof, T. C. & Powell, C. M. (2010). Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J Neurosci 6 30 2115 29
  15. 15. Boucard A. A. Chubykin A. A. Comoletti D. Taylor P. Südhof T. C. 2005A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to alpha- and beta-neurexins. Neuron 48 2 229 36
  16. 16. Braun A. R. Randolph C. Stoetter B. Mohr E. Cox C. Vladar K. Sexton R. Carson R. E. Herscovitch P. Chase T. N. 1995The functional neuroanatomy of Tourette’s syndrome: an FDG-PET Study. II: Relationships between regional cerebral metabolism and associated behavioral and cognitive features of the illness. Neuropsychopharmacology 13 2 151 68
  17. 17. Buckner R. Andrews-Hanna J. Schacter D. 2008The brain’s default network. Ann N Y Acad Sci 1124 1 38
  18. 18. Careaga M. Van de Water J. Ashwood P. 2010Immune dysfunction in autism: a pathway to treatment. Neurotherapeutics 7 3 283 92
  19. 19. Carlsson M. L. 2001On the role of prefrontal cortex glutamate for the antithetical phenomenology of obsessive compulsive disorder and attention deficit hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry 25 1 5 26
  20. 20. Cheng S. B. Amici S. A. Ren X. Q. Mc Kay S. B. Treuil M. W. Lindstrom J. M. Rao J. Anand R. 2009Presynaptic targeting of alpha4beta 2 nicotinic acetylcholine receptors is regulated by neurexin-1beta. J Biol Chem 284 35 23251 9
  21. 21. Chez M. G. Dowling T. Patel P. B. Khanna P. Kominsky M. 2007Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol 36 6 361 5
  22. 22. Chih B. Afridi S. K. Clark L. Scheiffele P. 2004Disorder-associated mutations lead to functional inactivation of neuroligins. Hum Mol Genet 13 14 1471 7
  23. 23. Chih B. Gollan L. Scheiffele P. 2006Alternative splicing controls selective trans-synaptic interactions of the neuroligin neurexin complex. Neuron 51 2 171 8
  24. 24. Chubykin A. A. Atasoy D. Etherton M. R. Brose N. Kavalali E. T. Gibson J. R. Südhof T. C. 2007Activity dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron 54 6 919 31
  25. 25. Clementi G. C. 2004Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 74 363 96
  26. 26. Coe J. W. Brooks P. R. Vetelino M. G. Wirtz M. C. Arnold E. P. Huang J. Sands S. B. Davis T. I. Lebel L. A. Fox C. B. Shrikhande A. Heym J. H. Schaeffer E. Rollema H. Lu Y. Mansbach R. S. Chambers L. K. Rovetti C. C. Schulz D. W. Tingley F. D. 3rd O’Neill B. T. 2005Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation.J Med Chem 48 3474 7
  27. 27. Comoletti D. De Jaco A. Jennings L. L. Flynn R. E. Gaietta G. Tsigelny I. Ellisman M. H. Taylor P. 2004The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. J Neurosci 24 20 4889 93
  28. 28. Conroy W. G. Nai Q. Ross B. Naughton G. Berg D. K. 2007Postsynaptic neuroligin enhances presynaptic inputs at neuronal nicotinic synapses. Dev Biol 307 1 79 91
  29. 29. Cook E. H. Scherer S. W. 2008Copy-number variations associated with neuropsychiatric conditions. Nature 455 7215 919 23
  30. 30. Corbett B. A. Mendoza S. Abdullah M. Wegelin J. A. Levine S. 2006Cortisol circadian rhythms and response to stress in children with autism. Psychoneuroendocrinology 31 1 59 68
  31. 31. Couey J. J. Meredith R. M. Spijker S. Poorthuis R. B. Smit A. B. Brussaard A. B. Mansvelder H. D. 2007Distributed network actions by nicotine increase the threshold for spike-timing-dependent plasticity in prefrontal cortex. Neuron 54 1 73 87
  32. 32. Courchesne E. Pierce K. Schumann C. M. Redcay E. Buckwalter J. A. Kennedy D. P. Morgan J. 2007Mapping early brain development in autism. Neuron 56 2 399 413
  33. 33. Court J. Spurden D. Lloyd S. Mc Keith I. Ballard C. Cairns N. Kerwin R. Perry R. Perry E. 1999Neuronal nicotinic receptors in dementia with Lewy bodies and schizophrenia: -bungarotoxin and nicotinic binding in thalamus. J Neurochem 73 1590 7
  34. 34. Court J. Martin-Ruiz C. Piggott M. Spurden D. Griffiths M. Perry E. 2001Nicotinic receptor abnormalities in Alzheimer’s disease. Biol Psychiatry 49 175 84
  35. 35. Coury D. 2010Medical treatment of autism spectrum disorders. Curr Opin Neurol 23 2 131 6
  36. 36. Craig A. M. Kang Y. 2007Neurexin-neuroligin signaling in synapse development. Curr Opin Neurobiol 17 1 43 52
  37. 37. Dajas-Bailador F. A. Heimala K. Wonnacott S. 2003The allosteric potentiation of nicotinic acetylcholine receptors by galantamine is transduced into cellular responses in neurons: Ca2+ signals and neurotransmitter release. Mol Pharmacol 64 1217 1226
  38. 38. Dalack G. W. Becks L. Hill E. Pomerleau O. F. Meador-Woodruff J. H. 1999Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia. Neuropsychopharmacology 21 195 202
  39. 39. De Fusco M. Becchetti A. Patrignani A. Annesi G. Gambardella A. Quattrone A. Ballabio A. Wanke E. Casari G. 2000The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat Genet 26 3 275 6
  40. 40. de Wit J. Sylwestrak E. O’Sullivan M. L. Otto S. Tiglio K. Savas J. N. Yates J. R. 3rd Comoletti D. Taylor P. Ghosh A. 2009LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation. Neuron 64 6 799 806
  41. 41. Dean C. Dresbach T. 2006Neuroligins and neurexins: linking cell adhesion, synapse formation and cognitive function. Trends Neurosci 29 1 21 9
  42. 42. Dolle F. Valette H. Hinnen F. Vaufrey F. Demphel S. Coulon C. et al. 2001Synthesis and preliminary evaluation of a carbon-11-labelled agonist of the 7 nicotinic acetylcholine receptor. J Labelled Cpd Radiopharm 44 785 95
  43. 43. Dudanova I. Sedej S. Ahmad M. Masius H. Sargsyan V. Zhang W. Riedel D. Angenstein F. Schild D. Rupnik M. Missler M. 2006Important contribution of alpha-neurexins to Ca2+-triggered exocytosis of secretory granules. J Neurosci 26 41 10599 613
  44. 44. Dudanova I. Tabuchi K. Rohlmann A. Südhof T. C. Missler M. 2007Deletion of alpha-neurexins does not cause a major impairment of axonal pathfinding or synapse formation. J Comp Neurol 502 2 261 74
  45. 45. Etherton M. R. Blaiss C. A. Powell C. M. Südhof T. C. 2009Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc Natl Acad Sci U S A 106 42 17998 8003
  46. 46. Falk L. Nordberg A. Seiger A. ̊. Kjældgaard A. Hellstro-Lindahl ̈. m. E. 2003Higher expression of 7 nicotinic acetylcholine receptors in human fetal compared to adult brain. Dev Brain Res 142 151 60
  47. 47. Feng J. Schroer R. Yan J. Song W. Yang C. Bockholt A. Cook E. H. Jr Skinner C. Schwartz C. E. Sommer S. S. 2006High frequency of neurexin 1beta signal peptide structural variants in patients with autism. Neurosci Lett 409 1 10 3
  48. 48. Fombonne E. 1999The epidemiology of autism: a review. Psychol Med 29 4 769 86
  49. 49. Frazier C. J. Buhler A. V. Weiner J. L. Dunwiddie T. V. 1998aSynaptic potentials mediated via alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in rat hippocampal interneurons. J Neurosci. 18 8228 8235
  50. 50. Frazier C. J. Rollins Y. D. Breese C. R. Leonard S. Freedman R. Dunwiddie T. V. 1998bAcetylcholine activates an alpha-bungarotoxin-sensitive nicotinic current in rat hippocampal interneurons, but not pyramidal cells, J Neurosci 18 1187 1195
  51. 51. Freedman R. Hall M. Adler L. E. Leonard S. 1995Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 38 22 33
  52. 52. Gai X. Xie H. M. Perin J. C. Takahashi N. Murphy K. Wenocur A. S. D’arcy M. O’Hara R. J. Goldmuntz E. Grice D. E. Shaikh T. H. Hakonarson H. Buxbaum J. D. Elia J. White P. S. 2011Rare structural variation of synapse and neurotransmission genes in autism. Mol Psychiatry Mar 1. [Epub ahead of print].
  53. 53. Gao Y. Horti A. G. Kuwabara H. Ravert H. T. Hilton J. Holt D. P. et al. 2007Derivatives of (-)-7-methyl-2-(5-(pyridinyl)pyridin-3- yl)-7-azabicyclo[2.2.1]heptane are potential ligands for positron emission tomography imaging of extrathalamic nicotinic acetylcholine receptors. J Med Chem 50 16 3814 3824
  54. 54. Gao Y. Kuwabara H. Spivak C. E. Xiao Y. Kellar K. Ravert H. T. et al. 2008Discovery of (-)-7-methyl-2-exo-[3’-(6-[18F] fluoropyridin-2-yl)-5’-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (alpha4beta2-nAChR) with optimal positron emission tomography imaging properties. J Med Chem 51 15 4751 4764
  55. 55. Garrity A. G. Pearlson G. D. Mc Kiernan K. Lloyd D. Kiehl K. A. Calhoun V. D. 2007Aberrant “default mode” functional connectivity in schizophrenia. Am J Psychiatry 164 450 457
  56. 56. Gauthier, J., Siddiqui, T. J., Huashan, P., Yokomaku, D., Hamdan, F. F., Champagne, N., Lapointe, M., Spiegelman, D., Noreau, A., Lafrenière, R. G., Fathalli, F., Joober, R., Krebs, M. O., Delisi, L. E., Mottron, L., Fombonne, E., Michaud, J. L., Drapeau, P., Carbonetto, S., Craig, A. M. & Rouleau, G. A. (2011). Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Hum Genet. 2011 Mar 22. [Epub ahead of print
  57. 57. Geschwind D. H. 2009Advances in autism. Annu Rev Med 60 367 80
  58. 58. Gillberg C. Billstedt E. 2000Autism and Asperger syndrome: coexistence with other clinical disorders. Acta Psychiatr Scand 102 321 330
  59. 59. Gilman S. R. Iossifov I. Levy D. Ronemus M. Wigler M. Vitkup D. 2011Rare De Novo Variants Associated with Autism Implicate a Large Functional Network of Genes Involved in Formation and Function of Synapses. Neuron 70 5 898 907
  60. 60. Glessner J. T. Wang K. Cai G. Korvatska O. Kim C. E. Wood S. Zhang H. Estes A. Brune C. W. Bradfield J. P. Imielinski M. Frackelton E. C. Reichert J. Crawford E. L. Munson J. Sleiman P. M. Chiavacci R. Annaiah K. Thomas K. Hou C. Glaberson W. et al. 2009Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459 569 573
  61. 61. Gogolla N. Leblanc J. J. Quast K. B. Südhof T. Fagiolini M. Hensch T. K. 2009Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord 1 2 172 181
  62. 62. Graf E. R. Zhang X. Jin S. X. Linhoff M. W. Craig A. M. 2004Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 119 1013 1026
  63. 63. Granon S. Faure P. Changeux J. P. 2003Executive and social behaviors under nicotinic receptor regulation. Proc Natl Acad Sci U S A 100 16 9596 601
  64. 64. Gunnell D. Irvine D. Wise L. Davies C. Martin R. M. 2009Varenicline and suicidal behaviour: a cohort study based on data from the General Practice Research Database. BMJ 339:b3805 EOF
  65. 65. Hashimoto K. Nishiyama S. Ohba H. Matsuo M. Kobashi T. Takahagi M. et al. 2008C]CHIBA-1001 as a novel PET ligand for α7 nicotinic receptors in the brain: a PET study in conscious monkeys. PLoS ONE 3:e3231.
  66. 66. Hata, Y., Butz, S. & Südhof, T. C. (1996). CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. J Neurosci 8 16 2488 94
  67. 67. Hoda J. C. Wanischeck M. Bertrand D. Steinlein O. K. 2009Pleiotropic functional effects of the first epilepsy-associated mutation in the human CHRNA2 gene. FEBS Lett 583 10 1599 604
  68. 68. Horti A. G. Gao Y. Kuwabara H. Dannals R. F. 2010Development of radioligands with optimized imaging properties for quantification of nicotinic acetylcholine receptors by positron emission tomography. Life Sci 86(15-16):575 EOF 584 EOF
  69. 69. Inta D. Vogt M. A. Lima-Ojeda J. M. Pfeiffer N. Schneider M. Gass P. 2011Lack of long-term behavioral alterations after early postnatal treatment with tropisetron: Implications for developmental psychobiology. Pharmacol Biochem Behav 99 1 35 41
  70. 70. Jamain S. Quach H. Betancur C. Råstam M. Colineaux C. Gillberg I. C. Soderstrom H. Giros B. Leboyer M. Gillberg C. Bourgeron T. Paris Autism. Research International. Sibpair Study. 2003Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 34 1 27 9
  71. 71. Jamain S. Radyushkin K. Hammerschmidt K. Granon S. Boretius S. Varoqueaux F. Ramanantsoa N. Gallego J. Ronnenberg A. Winter D. Frahm J. Fischer J. Bourgeron T. Ehrenreich H. Brose N. 2008Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc Natl Acad Sci U S A 105 5 1710 5
  72. 72. Kang, Y., Zhang, X., Dobie, F., Wu, H. & Craig, A. M. (2008). Induction of GABAergic postsynaptic differentiation by alpha-neurexins. J Biol Chem 4 283 2323 34
  73. 73. Kas M. J. Fernandes C. Schalkwyk L. C. Collier D. A. 2007Genetics of behavioural domains across the neuropsychiatric spectrum; of mice and men. Mol Psychiatry 12 4 324 30
  74. 74. Kihara T. Shimohama S. Sawada H. Kimura J. Kume T. Kochiyama H. Maeda T. Akaike A. 1997Nicotinic receptor stimulation protects neurons against beta-amyloid toxicity. Ann Neurol 42 159 63
  75. 75. Kihara T. Shimohama S. Urushitani M. Sawada H. Kimura J. Kume T. Maeda T. Akaike A. 1998Stimulation of alpha4beta2 nicotinic acetylcholine receptors inhibits beta-amyloid toxicity. Brain Res 792 331 4
  76. 76. Kihara T. Shimohama S. Sawada H. Honda K. Nakamizo T. Shibasaki H. Kume T. Akaike A. 2001alpha 7 Nicotinic Receptor Transduces Signals to Phosphatidylinositol 3-Kinase to Block A beta-Amyloid-induced Neurotoxicity. J Biol Chem 276 13541 6
  77. 77. Kim H. G. Kishikawa S. Higgins A. W. Seong I. S. Donovan D. J. Shen Y. Lally E. Weiss L. A. Najm J. Kutsche K. Descartes M. Holt L. Braddock S. Troxell R. Kaplan L. Volkmar F. Klin A. Tsatsanis K. Harris D. J. Noens I. Pauls D. L. Daly M. J. Mac Donald. M. E. Morton C. C. Quade B. J. Gusella J. F. 2008Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet 82 1 199 207
  78. 78. Kirov G. Rujescu D. Ingason A. Collier D. A. O’Donovan M. C. Owen M. J. 2009Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr Bull 35 5 851 4
  79. 79. Kitagawa H. Takenouchi T. Azuma R. Wesnes K. Kramer W. Clody D. Burnett A. L. 2003Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers. Neuropsychopharmacology 28 542 551
  80. 80. Ko J. Fuccillo M. V. Malenka R. C. Südhof T. C. 2009LRRTM2 functions as a neurexin ligand in promoting excitatory synapse formation. Neuron 64 6 791 8
  81. 81. Konstantareas M. M. Homatidis S. 1999Chromosomal abnormalities in a series of children with autistic disorder. J Autism Dev Disord 29 275 285
  82. 82. Langen M. Durston S. Kas M. J. van Engeland H. Staal W. G. 2011The neurobiology of repetitive behavior: … and men. Neurosci and Biobehavioral Rev 35 356 65
  83. 83. Laumonnier F. Bonnet-Brilhault F. Gomot M. Blanc R. David A. Moizard M. P. Raynaud M. Ronce N. Lemonnier E. Calvas P. Laudier B. Chelly J. Fryns J. P. Ropers H. H. Hamel B. C. Andres C. Barthélémy C. Moraine C. Briault S. 2004X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum Genet 74 3 552 7
  84. 84. Lee M. Martin-Ruiz C. Graham A. Court J. Jaros E. Perry R. Iversen P. Bauman M. Perry E. 2002Nicotinic receptor abnormalities in the cerebellar cortex in autism. Brain 125(Pt 7):1483 EOF 95 EOF
  85. 85. Lee S. W. Lee J. G. Lee B. J. Kim Y. H. 2007A 12-week, double-blind, placebo-controlled trial of galantamine adjunctive treatment to conventional antipsychotics for the cognitive impairments in chronic schizophrenia. Int Clin Psychopharm 22 63 68
  86. 86. Léna C. Popa D. Grailhe R. Escourrou P. Changeux J. P. Adrien J. 2004Beta2-containing nicotinic receptors contribute to the organization of sleep and regulate putative micro-arousals in mice. J Neurosci 24 25 5711 8
  87. 87. Levin E. D. Simon B. B. 1998Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology 138(3-4):217 EOF 30 EOF
  88. 88. Levitt P. Campbell D. B. 2009The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders. J Clin Invest 119 4 747 54
  89. 89. Levy D. Ronemus M. Yamrom B. Lee Y. Leotta A. Kendall J. et al. 2011Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders. Neuron 70 5 886 897
  90. 90. Levy S. E. Mandell D. S. Schultz R. T. 2009Autism. Lancet 374 9701 1627 38
  91. 91. Lipton S. A. Frosch M. P. Phillips M. D. Tauck D. L. Aizenman E. 1998Nicotinic antagonists enhance process outgrowth by rat retinal ganglion cells in culture. Science 239 1293 1296
  92. 92. Lisé, M. F. & El-Husseini, A. (2006). The neuroligin and neurexin families: from structure to function at the synapse. Cell Mol Life Sci 63(16):1833-4916 63 1833 49
  93. 93. Lindstrom J. 1996Neuronal nicotinic acetylcholine receptors. Ion Channels 4 377 450
  94. 94. Lindstrom J. 1997Nicotinic acetylcholine receptors in health and disease. Mol. Neurobiol 15 193 222
  95. 95. López-Valdés H. E. García-Colunga J. Miledi R. 2002Effects of clomipramine on neuronal nicotinic acetylcholine receptors. Eur J Pharmacol 444(1-2):13 EOF 9 EOF
  96. 96. Marshall C. R. Noor A. Vincent J. B. Lionel A. C. Feuk L. Skaug J. Shago M. Moessner R. Pinto D. Ren Y. Thiruvahindrapduram B. Fiebig A. Schreiber S. Friedman J. CE Ketelaars Vos. Y. J. Ficicioglu C. Kirkpatrick S. Nicolson R. Sloman L. Summers A. CA Gibbons Teebi. A. Chitayat D. Weksberg R. Thompson A. Vardy C. Crosbie V. Luscombe S. Baatjes R. Zwaigenbaum L. Roberts W. Fernandez B. Szatmari P. Scherer S. W. 2008Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82 2 477 88
  97. 97. Martin-Ruiz C. M. Lee M. Perry R. H. Baumann M. Court J. A. Perry E. K. 2004Molecular analysis of nicotinic receptor expression in autism. Brain Res Mol Brain Res 123(1-2):81 EOF 90 EOF
  98. 98. Marutle A. Zhang X. Court J. Piggott M. Johnson M. Perry R. Perry E. Nordberg A. 2001Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia. J Chem Neuroanat 22 115 26
  99. 99. Maskos U. Molles B. E. Pons S. Besson M. Guiard B. P. Guilloux J. P. Evrard A. Cazala P. Cormier A. Mameli-Engvall M. Dufour N. Cloëz-Tayarani I. Bemelmans A. P. Mallet J. Gardier A. M. David V. Faure P. Granon S. Changeux J. P. 2005Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436 7047 103 7
  100. 100. Mc Clure J. B. Swan G. E. Jack L. Catz S. L. Zbikowski S. M. Mc Afee T. A. Deprey M. Richards J. Javitz H. 2009Mood, side-effects and smoking outcomes among persons with and without probable lifetime depression taking varenicline. J Gen Intern Med 24 5 563 9
  101. 101. Mc Gehee D. S. Role L. W. 1996Presynaptic ionotropic receptors. Curr Opin Neurobiol 6 342 349
  102. 102. Merikangas A. K. Corvin A. P. Gallagher L. 2009Copy-number variants in neurodevelopmental disorders: promises and challenges. Trends Genet 25 12 536 44
  103. 103. Messi M. L. Renganathan M. Grigorenko E. Delbono O. 1997Activation of alpha7 nicotinic acetylcholine receptor promotes survival of spinal cord motoneurons. FEBS Lett 411 32 8
  104. 104. Mihalak K. B. Carroll F. I. Luetje C. W. 2006Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors. Mol Pharmacol 70 3 801 5
  105. 105. Miller D. T. Shen Y. Weiss L. A. Korn J. Anselm I. Bridgemohan C. et al. 2009Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet. 46 4 242 8
  106. 106. Mineur Y. S. Picciotto M. R. 2010Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis. Trends Pharmacol Sci 31 12 580 6
  107. 107. Missler M. Südhof T. C. 1998Neurexins: three genes and 1001 products. Trends Genet 14 1 20 6
  108. 108. Missler M. Zhang W. Rohlmann A. Kattenstroth G. Hammer R. E. Gottmann K. Südhof T. C. 2003Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature 423 6943 939 48
  109. 109. Miwa J. M. Freedman R. Lester H. A. 2011Neural systems governed by nicotinic acetylcholine receptors: emerging hypotheses. Neuron. 70 1 20 33
  110. 110. Morgan J. T. Chana G. Pardo C. A. Achim C. Semendeferi K. Buckwalter J. Courchesne E. Everall I. P. 2010Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol Psychiatry 68 4 368 76
  111. 111. Nam C. I. Chen L. 2005Postsynaptic assembly induced by neurexin-neuroligin interaction and neurotransmitter. Proc Natl Acad Sci USA 102 17 6137 42
  112. 112. Newhouse P. A. Kelton M. 2000Nicotinic systems in central nervous systems disease: degenerative disorders and beyond. Pharm Acta Helv 74(2-3):91 EOF 101 EOF
  113. 113. Newhouse P. Singh A. Potter A. 2004Nicotine and nicotinic receptor involvement in neuropsychiatric disorders. Curr Top Med Chem 4 3 267 82
  114. 114. Niaura R. Jones C. Kirkpatrick P. 2006Varenicline. Nat Rev Drug Discov 5 537 8
  115. 115. Nicolson R. Craven-Thuss B. Smith J. 2006A prospective, open-label trial of galantamine in autistic disorder. J Child Adolesc Psychopharmacol 16 5 621 9
  116. 116. Nussbaum J. Xu Q. Payne T. J. Ma J. Z. Huang W. Gelernter J. Li M. D. 2008Significant association of the neurexin-1 gene (NRXN1) with nicotine dependence in European- and African-American smokers. Hum Mol Genet 17 11 1569 77
  117. 117. Ochoa E. L. Lasalde-Dominicci J. 2007Cognitive deficits in schizophrenia: Focus on neuronal nicotinic acetylcholine receptors and smoking. Cell Mol Neurobiol 27 5 609 639
  118. 118. Ogawa M. Tatsumi R. Fujio M. Katayama J. Magata Y. 2006Synthesis and evaluation of [125I]I-TSA as a brain nicotinic acetylcholine receptor α7 subtype imaging agent. Nucl Med Biol 33 311 36
  119. 119. Papke R. L. Trocmé-Thibierge C. Guendisch D. Al Rubaiy. S. A. Bloom S. A. 2011Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists. J Pharmacol Exp Ther 337 2 367 79
  120. 120. Pasquini M. Garavini A. Biondi M. 2005Nicotine augmentation for refractory obsessive-compulsive disorder. A case report. Prog Neuropsychopharmacol Biol Psychiatry 29 1 157 9
  121. 121. Perry E. K. Lee M. L. Martin-Ruiz C. M. Court J. A. Volsen S. G. Merrit J. Folly E. Iversen P. E. Bauman M. L. Perry R. H. Wenk G. L. 2001Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain. Am J Psychiatry 158 7 1058 66
  122. 122. Pimlott S. L. Piggott M. Owens J. Greally E. Court J. A. Jaros E. Perry R. H. Perry E. K. Wyper D. 2004Nicotinic acetylcholine receptor distribution in Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease, and vascular dementia: In vitro binding study using 5-[125I]-A-85380. Neuropsychopharmacology 29 1 108 116
  123. 123. Pomper M. G. Phillips E. Fan H. Mc Carthy D. J. Keith R. A. Gordon J. C. Scheffel U. Dannals R. F. Musachio J. L. 2005Synthesis and biodistribution of radiolabeled 7 nicotinic acetylcholine receptor ligands. J Nucl Med 46 326 34
  124. 124. Poulopoulos A. Aramuni G. Meyer G. Soykan T. Hoon M. Papadopoulos T. Zhang M. Paarmann I. Fuchs C. Harvey K. Jedlicka P. Schwarzacher S. W. Betz H. Harvey R. J. Brose N. Zhang W. Varoqueaux F. 2009Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin. Neuron 63 5 628 42
  125. 125. Potter A. Corwin J. Lang J. Piasecki M. Lenox R. Newhouse P. A. 1999Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer’s disease. Psychopharmacology 142 4 334 42
  126. 126. Pugh P. C. Berg D. K. 1994Neuronal acetylcholine receptors that bind alpha-bungarotoxin mediate neurite retraction in a calcium-dependent manner, J Neurosci 14 889 896
  127. 127. Pugh P. C. Margiotta J. F. 2000Nicotinic acetylcholine receptor agonists promote survival and reduce apoptosis of chick ciliary ganglion neurons. Mol Cell Neurosci 15 113 22
  128. 128. Ramocki M. B. Zoghbi H. Y. 2008Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455 7215 912 8
  129. 129. Rojas, S., Martín, A., Arranz, M. J., Pareto, D., Purroy, J., Verdaguer, E., Llop, J., Gómez, V., Gispert, J.D., Millán, O., Chamorro, A. & Planas, A.M. (2007) Imaging brain inflammation with [(11)C]PK11195 by PET and induction of the peripheral-type benzodiazepine receptor after transient focal ischemia in rats. J Cereb Blood Flow Metab 12 27 1975 86
  130. 130. Rosas-Ballina M. Tracey K. J. 2009The neurology of the immune system: neural reflexes regulate immunity. Neuron 64 1 28 32
  131. 131. Ross B. S. Conroy W. G. 2008Capabilities of neurexins in the chick ciliary ganglion. Dev Neurobiol. 68 3 409 19
  132. 132. Ross S. A. Wong J. Y. Clifford J. J. Kinsella A. Massalas J. S. Horne M. K. Scheffer I. E. Kola I. Waddington J. L. Berkovic S. F. Drago J. 2000Phenotypic characterization of an alpha 4 neuronal nicotinic acetylcholine receptor subunit knock-out mouse. J Neurosci. 20 17 6431 41
  133. 133. Rubenstein J. Merzenich M. 2003Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes, Brain, and Behavior 2 5 255 267
  134. 134. Samochocki M. Höffle A. Fehrenbacher A. Jostock R. Ludwig J. Christner C. Radina M. Zerlin M. Ullmer C. Pereira E. F. R. Lübert H. Albuquerque E. X. Maelicke A. 2003Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. J Pharmacol Exp Ther 305 1024 1036
  135. 135. Sanberg P. R. Silver A. A. Shytle R. D. Philipp M. K. Cahill D. W. Fogelson H. M. Mc Conville B. J. 1997Nicotine for the treatment of Tourette’s syndrome. Pharmacol Ther 74 1 21 5
  136. 136. Sargent P. B. 1993The diversity of neuronal nicotinic acetylcholine receptors. Annu Rev Neurosci 16 403 443
  137. 137. Schilström B. Ivanov V. B. Wiker C. Svensson T. H. 2007Galantamine enhances dopaminergic neurotransmission in vivo via allosteric potentiation of nicotinic acetylcholine receptors. Neuropsychopharmacology 32 43 53
  138. 138. Schubert M. X. Young K. A. Hicks P. B. 2006Galantamine improves cognition in schizophrenic patients stabilized on risperidone. Biol Psychiatry 60 530 533
  139. 139. Shiina A. Shirayama Y. Niitsu T. Hashimoto T. Yoshida T. Hasegawa T. Haraguchi T. Kanahara N. Shiraishi T. Fujisaki M. Fukami G. Nakazato M. Iyo M. Hashimoto K. 2010A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia. Ann Gen Psychiatry 24(9):27 EOF
  140. 140. Sokol D. K. Chen D. Farlow M. R. Dunn D. W. Maloney B. Zimmer J. A. Lahiri D. K. 2006High levels of Alzheimer beta-amyloid precursor protein (APP) in children with severely autistic behavior and aggression. J Child Neurol 21 6 444 9
  141. 141. Steinlein O. K. 2002Nicotinic acetylcholine receptors and epilepsy. Curr Drug Targets CNS Neurol Disord 1 4 443 8
  142. 142. Südhof T. C. 2008Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455 7215 903 11
  143. 143. Szatmari P. Paterson A. D. Zwaigenbaum L. Roberts W. Brian J. Liu X. Q. et al. Autism Genome Project Consortium. (2007Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39 3 319 28
  144. 144. Siddiqui T. J. Pancaroglu R. Kang Y. Rooyakkers A. Craig A. M. 2010LRRTMs and neuroligins bind neurexins with a differential code to cooperate in glutamate synapse development. J Neurosci 30 7495 7506
  145. 145. Tabuchi K. Blundell J. Etherton M. R. Hammer R. E. Liu X. Powell C. M. Sudhof T. C. 2007A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318 71 76
  146. 146. Takata K. Kitamura Y. Saeki M. Terada M. Kagitani S. Kitamura R. Fujikawa Y. Maelicke A. Tomimoto H. Taniguchi T. Shimohama S. 2010Galantamine-induced amyloid-{beta} clearance mediated via stimulation of microglial nicotinic acetylcholine receptors. J Biol Chem 285 51 40180 91
  147. 147. Taly A. Corringer P. J. Guedin D. Lestage P. Changeux J. P. 2009Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nat Rev Drug Discov 8 9 733 50
  148. 148. Tapper A. R. Mc Kinney S. L. Nashmi R. Schwarz J. Deshpande P. Labarca C. Whiteaker P. Marks M. J. Collins A. C. Lester H. A. 2004Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization. Science 306 5698 1029 32
  149. 149. Toyohara J. Sakata M. Wu J. Ishikawa M. Oda K. Ishii K. et al. 2009Preclinical and the first clinical studies on [11C]CHIBA-1001 for mapping alpha7 nicotinic receptors by positron emission tomography. Ann Nucl Med 23 3 301 9
  150. 150. Tregellas J. R. Tanabe J. Rojas D. C. Shatti S. Olincy A. Johnson L. Martin L. F. Soti F. Kem W. R. Leonard S. Freedman R. 2011Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia. Biol Psychiatry 69 1 7 11
  151. 151. Uemura T. Lee S. J. Yasumura M. Takeuchi T. Yoshida T. Ra M. Taguchi R. Sakimura K. Mishina M. 2010Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum. Cell 141 6 1068 79
  152. 152. Vargas D. L. Nascimbene C. Krishnan C. Zimmerman A. W. Pardo C. A. 2005Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57 1 67 81
  153. 153. Varoqueaux F. Aramuni G. Rawson R. L. Mohrmann R. Missler M. Gottmann K. Zhang W. Südhof T. C. Brose N. 2006Neuroligins determine synapse maturation and function. Neuron 51 6 741 54
  154. 154. Wang D. Noda Y. Zhou Y. Mouri A. Mizoguchi H. Nitta A. Chen W. Nabeshima T. 2007The allosteric potentiation of nicotinic acetylcholine receptors by galantamine ameliorates the cognitive dysfunction in beta amyloid25-35 icv-injected mice: involvement of dopaminergic systems. Neuropsychopharmacology 32 1261 1271
  155. 155. Wang H. Yu M. Ochani M. Amella C. A. Tanovic M. Susarla S. Li J. H. Wang H. Yang H. Ulloa L. Al-Abed Y. Czura C. J. Tracey K. J. 2003Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421 6921 384 8
  156. 156. Westmark C. J. Westmark P. R. Beard A. M. Hildebrandt S. M. Malter J. S. 2008Seizure susceptibility and mortality in mice that over-express amyloid precursor protein. Int J Clin Exp Pathol. 1 2 157 68
  157. 157. Wilens, T. E., Biederman, J., Spencer, T. J., Bostic, J., Prince, J., Monuteaux, M. C., Soriano, J., Fine, C., Abrams, A., Rater, M. & Polisner, D. (1999) A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder. Am J Psychiatry 12 156 1931 7
  158. 158. Wills S. Cabanlit M. Bennett J. Ashwood P. Amaral D. G. Van de Water J. 2009Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain Behav Immun 23 1 64 74
  159. 159. Yan J. Noltner K. Feng J. Li W. Schroer R. Skinner C. Zeng W. Schwartz C. E. Sommer S. S. 2008Neurexin 1α structural variants associated with autism. Neurosci Lett 438 3 368 70
  160. 160. Ylisaukko-oja T. Rehnström K. Auranen M. Vanhala R. Alen R. Kempas E. Ellonen P. Turunen J. A. Makkonen I. Riikonen R. Nieminen-von Wendt. T. von Wendt. L. Peltonen L. Järvelä I. 2005Analysis of four neuroligin genes as candidates for autism. Eur J Hum Genet 13 285 1292
  161. 161. Zahir F. R. Baross A. Delaney A. D. Eydoux P. Fernandes N. D. Pugh T. Marra M. A. Friedman J. M. 2008A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha. J Med Genet 45 4 239 43
  162. 162. Zametkin A. J. Nordahl T. E. Gross M. King A. C. Semple W. E. Rumsey J. Hamburger S. Cohen R. M. 1990Cerebral glucose metabolism in adults with hyperactivity of childhood onset. N Engl J Med. 323 20 1361 6
  163. 163. Zhang Z. W. Coggan J. S. Berg D. K. 1996Synaptic currents generated by neuronal acetylcholine receptors sensitive to alpha-bungarotoxin. Neuron 17 1231 40
  164. 164. Zhang W. Rohlmann A. Sargsyan V. Aramuni G. Hammer R. E. Südhof T. C. Missler M. 2005Extracellular domains of alpha-neurexins participate in regulating synaptic transmission by selectively affecting N- and P/Q-type Ca2+ channels. J Neurosci. 25 17 4330 42
  165. 165. Zhang C. Atasoy D. Araç D. Yang X. Fucillo M. V. Robison A. J. Ko J. Brunger A. T. Südhof T. C. 2010Neurexins physically and functionally interact with GABA(A) receptors. Neuron 66 3 403 16

Written By

Rene Anand, Stephanie A. Amici, Gerald Ponath, Jordan I. Robson, Muhammad Nasir and Susan B. McKay

Submitted: November 10th, 2010 Published: August 17th, 2011