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Medicine » Mental and Behavioural Disorders and Diseases of the Nervous System » "Autism Spectrum Disorder - Recent Advances", book edited by Michael Fitzgerald , ISBN 978-953-51-2037-7, Published: April 2, 2015 under CC BY 3.0 license. © The Author(s).

Chapter 2

Neurotransmitter Systems in Autism Spectrum Disorder

By Fatih Hilmi Cetin, Huseyin Tunca, Esra Guney and Elvan Iseri
DOI: 10.5772/59122

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Neurotransmitter Systems in Autism Spectrum Disorder

Fatih Hilmi Cetin1, Huseyin Tunca1, Esra Guney1 and Elvan Iseri1

1. Introduction

Neurotransmitters, which connect neurons with each other, have key roles in normal development of brain, memory, motor activity and behavior regulation [1]. Based on these knowledge, neurotransmitter system dysfunction thought to be the cause of Autism Spectrum Disorder (ASD), by affecting neuronal cell migration, differentiation and synaptogenesis and eventually developmental processes of the brain [2, 3]. In pathophysiology of ASD many neurotransmitter systems has been investigated and dysfunction of these systems has been shown to be responsible. In the literature, neurotransmitters that are most commonly associated with the pathogenesis of ASD are, GABAergic, glutamatergic and serotonergic systems [4].


In order to maintain function and homeostasis of Central Nervous System (CNS) the balance between excitation and inhibition of neurons is very important. Main inhibitory neurotransmitter in the brain is gamma amino butyric acid (GABA) [5]. GABA is synthesized from glutamate by the enzyme glutamic acid decarbosilase (GAD) [6]. This enzyme has two isoforms known as GAD67 and GAD65, these are encoded by GAD1 and GAD2 gene. These enzymes different from each other in terms of the intracellular localization, expression, and enzymatic activity [7]. After GABA sythesized, it is taken to the vesicle by vesicular GABA transporter (VGATs) [8]. GABA is released to synaptic space under influence of Action Potential (AP) and binds to the GABAA and GABAC iyonotrophic receptors or metabotropic GABAB receptors [9]. The activity of GABA that is released to the synaptic space is ended by GABA transporters which are located at cell membrane (GAT) [10]. Finally GABA that is taken to the inside cell furtherly degrades by the transaminase or succinate semialdehide dehidrogenase enzymes [9].

GABA has a key role in the regulation of early developmental stages of cell migration, neuronal differentiation and stages of maturation [11]. Besides, formation of GABAergic system has a critical role in migration of GABAergic neurons and formation of glutamergic system mediated excitatory processes that regulate cortical inhibitory system [12]. Therefore, it is not suprising that especially in ASD and in many neurodevelopmental disorders GABAergic system is the main responsible [13, 14]. In addition, the high prevalence of epilepsy in patients with autism have made it worth to investigate GABA neurotransmitter system in individuals who has ASD [15].

Neurochemical abnormality that postulated to be associated with pathophysiology of ASD is the reduction in the expression of GAD65 and GAD67 which cause suppression of GABAergic inhibition [16]. Fatemi and his colleagues [17], in the cerebellum and parietal cortex of patients has shown significantly decrease in two isoforms of the rate-limiting enzyme which are responsible for the conversion of glutamate to GABA. Detection of low platelet GABA levels in children with ASD [18] and postmortem studies that illustrtaed significant reduction in GABAA and GABAB receptor subunit in various brain regions [19, 20] support the widespread dysfunction of GABAergic system in patients with ASD. Reduced production or signaling of GABA cause hyperexcitability state and leads to cognitive dysfunction [21]. Deletional mutations of genes encoded by chromosome 15q11-q13 which is some of the GABAA receptor subtype unites (GABRB3, GABRA5 and GABRG3) might be cause of reduction in GABAergic transmission, and these mutations have been suggested to be a risk factor ASD [14]. Also, many of the candidate genes associated with ASD are expressed in interneurons [22]. Antiepileptic agents, especially benzodiazepines has been used in ASD and epilepsy coexisted patients and they have shown to improve socialization and communication skills, though, in some cases, they lead to increased anxiety and aggression, because of this, the information mentioned above is not clear yet [23,24]. Lemonier and Ben-Ari [25] sugeested that the inhibition of Na / K / Cl transporter (NKCC1) lead intracellular increased Cl levels, so the GABAergic transmission will change depolarization to the hyperpolarization and in five ASD cases they get positive results after the treatment with NKCC1 inihbitor bumetanide. Then they carried out double blind randomized controlled clinical trial of bumetanide for treatment of ASD for 3 months of period in 54 patients, the results has shown to provide a significant improvement of ASD symptoms [26]. In utero exposure to valproate in mice model, has caused dissappearance of swicth between GABA excitation / inhibition and this problem has shown to lead the development of chronic chlorine deficits and autistic-like behavior [27]. Ion channels mutated mouse model which led to the reduced GABAergic transmission, and the corelation between ASD symptoms and reduced GABAergic transmission level and with benzodiazepine treatment autistic-like behavior to has shown to decrease [28].

As a result of animal model publications and studies conducted in patients with ASD has confirmed the hypothesis of "decreased GABAergic transmission in ASD patients". In future studies, to develop a new therapeutic agents, and to even prevent the disease focus should be directed on the GABA neurotransmitter system.

3. Glutamate

Glutamate is essential excitatory neurotransmitter of the central nervous system. It is synthesized from glutamine via glutaminase enzyme. There are two types which are iyontropic and metabotropic receptors. Metabotropic receptors (mGluR) are coupled with G protein and within the cell according to signaling pathways they divided 3 into subtypes: Group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3), Group III (mGluR4 and mGluR6-8). Group I works through activation of phospholipase C whereas Group II and Group III works through decreasing cyclic AMP level [29]. Ionotropic receptors which are coupled with ion-channel, have 3 sub-types: N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors. Kainat receptors located presynaptically at the hippocampus, stimulation of them reduce glutamatergic transmission [30]. Induction of AMPA receptors, these are associated with learning and memory, lead to the long-term potentiatio (LTP) and long-term depressio of (LTD) [31]. High levels of glutamate leading to overstimulation of NMDA receptors and cause a high amount of calcium influx, which is main responsible for excitotoxicity lead to the neuronal damage. Therefore, optimization of the level of glutamate in the synaptic cleft is critical. To protect post-synaptic neurons from excitotoxic effect the neuronal glutamate transporters which reside at the presynaptic membrane take back glutamate into cell from synaptic cleft. In final stage, glutamate is destroyed with GAD [1]. Balance between excitation / inhibition is crucial for synaptogenesis and plasticity, especially in first 3 years of life [32]. Blockade of NMDA receptors in the prenatal period initiates apoptosis in neurons [1].

From this point, glutamate plays a central role in shaping the architecture of the brain. Cell migration, maturation and developmental stages, such as synaptogenesis and neuroplastisicity is accomplished with the optimum glutamat transmission level [33, 34]. At the same time it is directly associated with cognitive processes such as memory and learning [35].

Glutamate receptors associated with ASD are highly expressed in the hippocampus and cerebellum [36]. For these reasons, the role of glutamatergic system in patiets with ASD has been substantially investigated, two opposite hypotheses regarding the role of this system have been proposed [37]. First hypotheses of ASD has been proposed hypoglutamatergic state [38, 39, 40], the second postulated the depletion of GABAergic inhibition excitation / inhibition rate which eventually lead to the hyperglutamatergic state [41, 42, 43]. Consistent with the hypothesis suggested that ASD is hypoglutamatergic disorder, in 1998 Carlsson has postulated decrease in glutamate signaling lead to activation of receptors at the cortical GABA interneurons and this state cause significant depression in excitator glutamate circuit [38, 44].

Other supportive evidence is hypoglutamatergic state in mouse models caused similiar presentation to ASD including inability to change behavior paradigm, limitation in habits and behavior [45] In a postmortem study patients with ASD has shown significant decrease in AMPA type 2 and 3 in cerebellum tissue [40].

Another hypothesis that might be surrogate to explain ASD is hypoglutamatergic state and associated cortical tissue hyperexcitability in spesific cortical areas. Some studies has demonstrated higher serum glutamate levels in individuals with autism [46]. Increased glutamate level probably connected with diminished GAD enzyme level [47, 48, 49]. This diminish also explain reduction in GABA transmission [50]. First study was done by Shimmura has illustrated higher serum glutamate levels and lower glutamine levels [51]. Secondly Shimmura et al. [52] has done another study they researched brain tissue from 7 postmortem ASD patients, they found higher levels of glutamate and glutamine levels at anterior cingulate cortex, interstingly levlels of glutaminase, glutamine synthase, and GAD were normal. As mentioned above ASD patients have high incidence of epilepsy, this is due to increase in glutamatergic activity [53, 54].

Animal models and conducted clinical studies in ASD subjects support hyperglutamatergic hypothesis. Silverman et al. [55] is conducted a study on ASD core symptoms observed mice model and found that GRN-529 (allosteric modulators of mGluR5 receptor) ameliorated all core symptoms of ASD. Another study conducted with AMPA receptor agonist (Ampakin) relieved symptoms of respiratory system on mice model with Rett syndrome [56]. Lamotrigine, which reduce glutamate transmission, has improved communication skills, socialization and behavior problems in 28 children diagnosed with ASD [57]. Ketamine, an NMDA receptor antagonist, has been shown to have a positive impact on focused attention in ASD cases [58].

Another NMDA receptor antagonist, memantine, significant improvement was observed on learning, language skills and in the areas of socialization in patients with ASD [59]. Recently, a randomized controlled study carried out, the memantine and risperidone receiving group were compared to placebo and risperidone receiving group, at the 10th week of treatment, memantine and risperidone received group better recovered compared to only risperidone received group in terms of the irritability, stereotypies and hyperactivity symptoms [60]. Recently, non-invasive brain imaging techniques such as magnetic resonance spectroscopy has enabled measurment of glutamate levels in brain tissue. Since first study was published in 2006 to date there were 15 studies done and conflicting results have been obtained [37]. In some studies, the anterior cingulate cortex [61] and auditory cortex [62] areas glutamate levels was increased compared to healthy controls, while in others there was no difference, and in the rest lower glutamate levels was observed [63, 64].

Some researchers thought these two hypotheses related to glutamatergic system are not completely opposite, some spesific cortical areas has increased excitatory / inhibitory ratio whereas in other regions, this ratio could turn opposite [44].

As a result, it is not clear yet whether the ASD individuals hyper or hypoglutamatergic, but it is clear that there is dysfunction in the glutamatergic system. New investigations has focused more in hyper-glutamatergic state and efforts are directed at glutamate receptor antagonismin order to develop new therapeutic agents. A better understanding of the glutamatergic system agents in the future will contribute to enlight ASD pathogenesis.

4. Serotonin

Serotonin is a neuromodulator which acts as a developmental signal [65]. Serotonin is synthesized by the enzyme triptophanhidroksilase which convert triptpohan to 5-hydroxy-tryptophan, and decarboksilation at the end [66]. Serotonin neurotransmitter system has critical role in the regulation of crucial steps of neuronal development such as cell proliferation, differentiation, migration, apoptosis synaptogenesis, neuronal and glial development [67, 68]. Serotonin system in the prefrontal cortex and temporal cortex regulates GABAergic inhibition, therefore it has played a role in the regulation of many aspects of cognitive functions [69].

Serotonin plays an important role in the development of social skills during gestational period and early childhood. Inadequate stimulation of serotonin in the early stages of life, can lead to the unpreventable abnormalities in serotonin metabolism in subsequent period of life. These defect may cause permanent problems in serotonin metabolism in people who have been deprived serotonin effects necessary for the brains especially early developmental stages of life. This is why, adequate levels of serotonin are necessary for the development of close relationships and social skills in the early stages of life [70]. Social skills and behavior have been shown to be associated with hippocampal neurogenesis in ASD individuals and because of that hippocampal abnormalities are found frequently [71]. Serotonin play a central regulating role in serotonin dependent neurogenesis activity in the hippocampus [72].

Pathophysiology of ASD has two main hypothesis for serotonin neurotransmitter systems, just like glutamate hypothesis. One widely accepted for a long time and confirmed for many times is hyperserotonin state and while the other one is hyposerotonin hypothesis which became prominent in recent years [66]. Two main findings of hyperserotonin hypothesis in patients with ASD are increased blood serotonin levels (my hiperserotone) and decreased brain serotonin levels [66]. The presence of hyperserotonemia in 25 to 50% of individuals with ASD is important to showing they may have abnormalities in the serotonergic pathway [73, 74,75].

Furthermore, first-degree relatives of individuals with ASD found to have hyperserotonemia, as well as parents of these kids more often showed the presence of serotonin associated psychiatric disorders, such as depression and obsessive-compulsive disorder [74, 76]. Other supportive evidence, brain serotonin level decreased and exacerbation of many repetitive behavior was observed (such as spinning, stepping, self-hit and shoot) with tryptophan poor diet (low-tryptophan diet) [77]. Serum levels of tryptophan to large neutral amino acid ratio was shown to be decreased in children with ASD. This rate is an indicative of presence of tryptophan for serotonin synthesis in the brain and this lower ratio demonstrate low tryptophan usability which might suggest one of the mechanisms associated with serotonergic dysfunction in ASD [78]. Another study demonstrated, after L-5-hydroxytryptophan administration young people with ASD, their blood serotonin levels increased, whereas in control group no difference was seen [79].

Severity of at least one specific behavioral problem in ASD is reported to be associated with 5HT1D receptor sensitivity [80]. Various studies have reported controversial results regarding association of serotonin transporter gene in ASD. In contrast, in accordance with the data regarding the transfer of serotonin transporter gene polymorphic alleles associated with the findings of the degree of the social and communicative deficits, these alleles instead of being risk factor for ASD they might change the severity of clinical presentation in autistic children [75].

Shown correlation between ASD and serotonin transporter gene and found mutations in genes encode rate-limiting enzyme in the catabolism of L-tryptophan such as 2,3 dioxygenase gene is thought to be responsible for increased serotonin levels [81]. There might be defect in the development of the serotonergic system in patients with ASD. Normally, the serotonin neurotransmitter system follows a pattern of age-related development, for example, developmental studies of serotonin receptor binding in monkeys showed that increment during infancy and throughout childhood, a prepubertal peak, and eventually slowly reduction during adolescence and early adulthood [82]. In humans at 6 year of age serotonin receptor binding is higher than neonatal period or 13-14 year of age [83]. This dynamic changes are impaired in ASD, at the beginning of childhood low serotonin levels are observed compared to normal baseline, but steadily increased from 2 to 15 years of age and reaches higher than adult levels [84, 85]. In various animal models when effect of higher levels of serotonin investigated particılarly in the development of somatosensory system, the deterioration in the formation of thalamo-cortical sensory circuits were observed [86]. Recently "ASD is a hyposerotonergic condition" hypothesis is worth to discuss. In a study of volunteer postmortem brain tissue of ASD patients examined, and the increase in number of serotonergic axons were observed [87].

This situation cannot be explained by the hypothesis of compensatory mechanisms which expected to result reduction of serotonergic axons in hyperserotonergic state [88]. In men with ASD, in one side of the brain of frontal region and thalamus, typically synthesis of serotonin was reduced, in opposite side of the brain of cerebellum, and dentate nucleus serotonin has been shown to be increased [70].

Several PET and SPECT studies in individuals with ASD has shown serotonin transporter binding amount decreased significantly in various brain regions (frontal cortex, cingulate, thalamus, etc..) [89, 90]. Other study was exhibited that low levels of blood serotonin in mothers of children with ASD compared to normal developing children's mother [91]. In another study, individuals with ASD were shown to have low levels of gene responsible for synthesis of serotonin [92]. Serotonergic drugs, the main symptoms of ASD respond less to treatment, but some are partially effective in the symptomatic treatment of patients with autism. These drugs include selective serotonin reuptake inhibitors (selective serotonin reuptake inhibitör=SSRI), 5-HT 2A receptor antagonists, tricyclic antidepressants and receptor antagonists (dopamin/5-HT) mix.

Mechanism of action of these treatments are unknown, but they are thought to act on the developmental defects in serotonergic pathways such as serotonin synthesis, catabolism, and transport-related dynamic abnormalities [93, 94].

As a result, the highest level of evidence for ASD relationship with monoamines is the serotonergic system. Hyperserotonemia in peripheral blood in individuals with ASD, despite the presence of opposite results, has been shown to be present in many studies. Low levels of serotonin in the brain tissue is the common finding of hyposerotonergic and hyperserotonergic hypothesis. Future studies will enlight reson for lower serotonin levels in the brain tissue and will open new horizons both for diagnosis and treatment.

5. Catecholamines

Evidence for the relationship of dopamine and norepinephrine with ASD was gathered from the studies reported decrease in DBH (Dopamine B Hydroxilase) activity and increased serum norepinephrine levels in children with autism and in their parents [95]. Findings increased catecholamine levels of the blood, urine, and cerebrospinal fluid in children with ASD [96, 97] as well as evidences sugested abnormal dopaminergic activity in the medial prefrontal cortex proposed abnormal cathecolaminergic activity [98]. Another supportive study has shown that, patients with ASD have increased urinary homovalinic acid level which is a degradation product of dopamine [99].

Robinson et al [100] demonstrated, mothers of children with ASD has low serum DBH levels and this interpreted to cause possible risk factor for ASD by creating a non-ideal intrauterine environment (leading to reduced norepinephrine and increased levels of dopamine). Study was done by using positron emission tomography (PET) in high-functioning ASD individuals has enligthened that increased activity of dopamine transporter (DAT) at the orbitofontal cortex region [89]. In a more detail study, Neale BM and his colleagues have found a de novo mutation of DAT gene (SLC6A3] in individuals with ASD [101].

6. Acetylcholine

Chemical and histochemical studies in the brains of individuals with ASD has shown loss of nicotinic receptors, in addition to that basal forebrain cholinergic neurons have been reported to be abnormally large and surplus [102]. A postmortem investigation of parietal neocortex showed reduced number of neuronal α-4 and β-2 nicotinic acetylcholine receptor (nAChR) subunit [103]. A while decreased cerebellar α-3/α-4 / β-2 nAChR ligand binding was detected, α-7 receptor subunit was exhibited compensatory increase [104].

Another study showed reduction in the expression of α-4 nAChR subunit in the frontal cortex whereas expression of α-4 nAChR subunit was found to increase in the cerebellum [105]. In another study, the α-7 nAChR subunit was determined to decreas especially in paraventricular nucleus and nucleus reuniens [106]. Postmortem samples taken from ASD individuals demonstrated significantly decreased α-7 receptor mRNA levels in frontal cortex [107]

Brain samples of cerebral cortex and basal forebrain choline acetyltransferase and acetylcholinesterase enzyme activity was measured, but no significant relationship was found with ASD. However, increased BDNF levels were detected which has affect on development and functions of cholinergic neurons in the basal forebrain [103]. Evidence of relationship between ASD and cholinergic circuits is still weak. Therefore extensive research in this area are needed.


1 - Choudhury PR, Lahiri S, Rajamma U. Glutamate mediated signaling in the pathophysiology of autism spectrum disorders. Pharmacology, Biochemistry and Behavior, 2012; 100:841–849.
2 - Kwong WH, Chan WY, Lee KK, Fan M, Yew DT. Neurotransmitters, neuropeptides and calcium binding proteins in developing human cerebellum: a review. Histochem J, 2000; 32:521–34.
3 - Chugani DC.Neurotransmitters. Autism spectrum disorders (ed: Amaral, Dawson ve Geshwind) Oxford University Press, 2011.
4 - Trottier G, Srivastava L, Walker CD. Etiology of infantile autism: a review of recent advances in genetic and neurobiological research. J Psychiatr Neurosci,1999; 24: 103-115.
5 - Hübner CA, Holthoff K. Anion transport and GABA signaling. Front Cell Neurosci, 2013; 7: 177.
6 - Pinal CS, Tobin AJ. Uniqueness and redundancy in GABA production. Perspect Dev Neurobiol, 1998; 5: 109–118.
7 - Buddhala C, Hsu CC, Wu JY. A novel mechanism for GABA synthesis and packaging into synaptic vesicles. Neurochem Int, 2009; 55: 9–12.
8 - Roth TC, Ladage LD, Freas C A, Pravosudov VV. Variation in memory and the hippocampus across populations from different climates: a common garden approach. Proc Biol Sci, 2012; 279: 402–410.
9 - Deidda G, Bozarth IF, Cancedda L. Modulation of GABAergic transmission in development and neurodevelopmental disorders: investigating physiology and pathology to gain therapeutic perspectives. Front Cell Neurosci, 2014; 8: 1-23.
10 - Lee TS, Bjornsen LP, Paz C, Kim JH, Spencer SS, Spencer DD et al. GAT1 and GAT3 expression are differently localized in the human epileptogenic hippocampus. Acta Neuropathol, 2006; 111: 351–363.
11 - Ben-Ari Y, Woodin MA, Sernagor E, Cancedda L, Vinay L, Rivera C et al (2012) Refuting the challenges of the developmental shift of polarity of GABA actions: GABA more exciting than ever! Front Cell Neurosci. 6: 35.
12 - Lewitt P, Eagleson KL, Powell EM. Regulation of neocortical interneuron development and the implications for neurodevelopmental disorders. Trends Neurosci, 2004; 27: 400-406.
13 - Di Cristo G, Pizzorusso T, Cancedda L, Sernagor E. GABAergic circuit development and its implication for CNS disorders. Neural Plast, 2011; 623-705.
14 - Coghlan S, Horder J, InksterB, Mendez MA, Murphy DG, Nutt DJ. GABA system dysfunction in autism and related disorders: from synapse to symptoms. Neurosci. Biobehav Rev, 2012; 36: 2044–2055.
15 - Brooks-Kayal A. Epilepsy and autism spectrum disorders:are there common developmental mechanisms? Brain Dev, 2010; 32: 731–738.
16 - Hussman JP. Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism. J Autism Dev Disord, 2001; 31: 247-248.
17 - Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR. Glutamic acid decarboxylase 65 and 67 kDA proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry, 2002; 52: 805-810.
18 - Rolf LH, Haarmann FY, Grotemeyer KH, Kehrer H. Serotonin and amino acid content in platelets of autistic children. Acta Psychiatrica Scandinavica, 1993; 87(5): 312-316.
19 - Fatemi SH, Reutiman TJ, Folsom TD, Thuras PD. GABA(A) receptor downregulation in brains of subjects with autism. J Autism Dev Disord, 2009; 39(2): 223-30.
20 - Oblak AL, Gibbs TT, Blatt GJ. Decreased GABAB receptors in the cingulate cortex and fusiform gyrus in autism. J Neurochemistry, 2010; 114(5): 1414-1423.
21 - Hensch TK, Fagiolini M, Mataga N, Stryker MP, Baekkeskov S, Kash SF. Local GABA circuit control of experience-dependent plasticity in developing visual cortex. Science, 1998; 282: 1504-1508.
22 - Xu X, Wells AB, O’Brien DR, Nehorai A, Dougherty JD. Cell type-specific expression analysis to identify putative cellular mechanisms for neurogenetic disorders. J. Neurosci, 2014; 34: 1420–1431.
23 - Di Martino A, Tuchman RF. Antiepileptic drugs: affective use in autism spectrum disorders. Pediatr Neurol, 2001; 25: 199–207.
24 - Marrosu F, Marrosu G, Rachel MG, Biggio G. Paradoxical reactions elicited by diazepam in children with classic autism. Funct Neurol, 1987; 2: 355–361.
25 - Lemonnier E, Ben-Ari Y. The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects. Acta Paediatr, 2010; 99:1885–1888.
26 - Lemonnier E, Degrez C, Phelep M, Tyzio R, Josse F, Grandgeorge M et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry, 2012; 2: 202.
27 - Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science 2014; 343:675–679.
28 - Han S, Tai C, Westenbroek RE, Yu FH, Cheah CS, Potter GB et al. Autistic like behaviour in Scn1a+/-mice and rescue by enhanced GABA mediated neurotransmission. Nature, 2012;489:385–390.
29 - Kew JN, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacol, 2005; 79: 4–29.
30 - Pinheiro P, Mulle C. Kainate receptors. Cell and Tissue Research, 2006; 326: 457–482.
31 - Whitlock JR, Heynen AJ, Shuler MG, Bear MF. Learning induces long-term potentiation in the hippocampus. Science, 2006; 313: 1093–1097.
32 - Oberman LM. mGluR antagonists and GABA agonists as novel pharmacological agents for the treatment of autism spectrum disorders. Expert Opinion on Investigational Drugs, 2012; 21:1819–1825.
33 - Mattson MP. Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann NY Acad Sci, 2008; 1144: 97–112.
34 - Lodge D. The history of the pharmacology and cloning of ionotropic glutamate receptors and the development of idiosyncratic nomenclature. Neuropharmacol, 2008; 56: 6–21.
35 - Manent JB, Represa A. Neurotransmitters and braimaturation: early paracrine actions of GABA and glutamate modulate neuronal migration. Neuroscientist, 2008;13: 268–79.
36 - Ozawa S, Kamiya H, Tsuzuki K. Glutamate receptors in the mammalian central nervous system. Prog Neurobiol, 1998; 54: 581–618.
37 - Rojas DC. The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. J Neural Transm, 2014.
38 - Carlsson ML. Hypothesis: is infantile autism a hypoglutamatergic disorder? Relevance of glutamate–serotonin interactions for pharmacotherapy. J Neural Transm, 1998; 105:525-535.
39 - Jamain S, Betancur C, Quach H, Philippe A, Fellous M, Giros B et al. Linkage and association of the glutamate receptor 6 gene with autism. Mol Psychiatry, 2002; 7(3):302-310.
40 - Purcell AE, Jeon OH, Zimmerman AW, Blue ME, Pevsner J. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology, 2001; 57: 1618-1628.
41 - Rubenstein JL, Merzenich MM. Model of autism: Increased ratio of excitation /inhibition in key neural systems. Genes Brain Behav, 2003;2: 255-267.
42 - Belmonte MK, Allen G, Beckel-Mitchener A, Boulanger LM, Carper RA, Webb SJ. Autism and abnormal development of brain connectivity. J Neurosci, 2004; 20: 9228-9231.
43 - Fatemi SH. The hyperglutamatergic hypothesis of autism. Prog Neuro psychopharmacol, Biol Psychiatry, 2008; 32:911.
44 - Polleux F, Lauder JM. Toward a developmental neurobiology of autism. Mental Retardation and Developmental Disabilities Research Review, 2004;10: 303-317.
45 - Nilsson M, Carlsson A, Markinhuhta KR, Sonesson C, Pettersson F, Gullme M, et al. The dopaminergic stabiliser ACR16 counteracts the behavioural primitivization induced by the NMDA receptor antagonist MK-801 in mice: implications for cognition. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:677–85
46 - Shinohe A, Hashimoto K, Nakamura K, Tsujii M, Iwata Y, Tsuchiya KJ, et al. Increased serum levels of glutamate in adult patients with autism. Prog Neuropsychopharmacol Biol Psychiatry, 2006; 30:1472–1477.
47 - Moreno-Fuenmayor H, Borjas L, Arrieta A, Valera V, Socorro-Candanoza L. Plasma excitatory amino acids in autism. Invest Clin, 1996; 37(2):113-28.
48 - Yip J, Soghomonian JJ, Blatt GJ.Decreased GAD67 mRNA levelsin cerebellar Purkinje cells in autism: “pathophysiological implications. Acta Neuropathol, 2007; 113: 559-568.
49 - Fatemi SH, Reutiman TJ, Folsom TD,Thuras PD. GABA(A) receptor downregulation in brains of subjects with autism. Journal of Autism andDevelopmental Disorders, 2009; 39, 223–230.
50 - Gaetz W, Bloy L, Wang DJ, Port RG, Blaskey L, Levy SE, et al. GABA estimation in the brains of children on the autism spectrum: Measurement precision and regional cortical variation. NeuroImage, 2014; 86:1–9.
51 - Shimmura C, Suda S, Tsuchiya KJ, Hashimoto K, Ohno K, Matsuzaki H, et al. Alteration of plasma glutamate and glutamine levels in children with high-functioning autism. PLoS One 6:e25340; 2011.
52 - Shimmura C, Suzuki K, Iwata Y, Tsuchiya KJ, Ohno K, Matsuzaki H,et al. Enzymes in the glutamate-glutamine cycle in the anterior cingulate cortex in postmortem brain of subjects with autism. Mol Autism, 2013; 4(1):6
53 - Gatto CL, Broadie K. Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models. Frontiers in Synaptic Neuroscience, 2010; 7:2–4.
54 - Hussman JP. Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism. J Autism Dev Disord, 2001; 31: 247-248.
55 - Silverman JL, Smith DG, Rizzo SJ, Karras MN, Turner SM, Tolu SS et al. Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Science Translational Medicine, 2012; 131:131–151.
56 - Silverman JL, Oliver CF, Karras MN, Gastrell PT, Crawley JN. AMPAKINE enhancement of social interaction in the BTBR mouse model of autism. Neuropharmacology, 2013; 64, 268–282.
57 - Belsito KM, Law PA, Kirk KS, Landa RJ, Zimmerman AW. Lamotrigine therapy for autistic disorder: a randomized, double-blind, placebo-controlled trial. J Autism Dev Disord 2001;31:175–81
58 - Shah S, Apuya J, Gopalakrishnan S, Martin T. Combination of oral ketamine and midazolam as a premedication for a severely autistic and combative patient. J Anesth 2009;23:126–8.
59 - Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M. Elavation of Tumor Necrosis Factor-alpha in Cerebrospinal Fluid of Autistic Children. Pediatr Neurol, 2007; 36: 361-365.
60 - Ghaleiha A, Asadabadi M, Mohammadi MR, Shahei M, Tabrizi M, Hajiaghaee R,et al. Memantine as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol, 2013; 16:783–789.
61 - Bejjani A, O'Neill J, Kim JA, Frew AJ, Yee VW, Ly R, et al. Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by 1H MRS and 1H MRSI. PLoS One 7:e38786, 2012.
62 - Brown MS, Singel D, Hepburn S, Rojas DC. Increased glutamate concentration in the auditory cortex of persons with autism and first-degree relatives: a 1H-MRS study. Autism Res 2013; 6:1–10.
63 - Bernardi S, Anagnostou E, Shen J, Kolevzon A, Buxbaum JD, Hollander E, et al. In vivo 1H-magnetic resonance spectroscopy study of the attentional networks in autism. Brain Res, 2011;1380:198–205.
64 - Horder J, Lavender T, Mendez MA, O’Gorman R. Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a 1H MRS study. Transl Psychiatry, 2013.
65 - Celada P, Puig MV, Artigas F. Serotonin modulation of cortical neurons and networks. Front Integr Neurosci, 2013; 7:25
66 - Yang CJ, Tan HP, Du YJ. The developmental disruptions of serotoninsignaling may involved in autism during early brain development. Neuroscience, 2014; 267C: 1–10.
67 - Lauder JM. Neurotransmitters as growth regulatory signals: Role of receptors and second messengers. Trends Neurosci,1993; 16: 233–240.
68 - Whitaker-Azmitia PM. Serotonin and brain development: Role in human developmental diseases. Brain Res Bull, 2001; 56: 479–485.
69 - Yan Z. Regulation of GABAergic inhibition by serotonin signaling in prefrontal cortex: molecular mechanisms and functional implications. Mol Neurobiol, 2002; 26: 203-216.
70 - Brasic JR. PET scanning in autism spectrum disorders., 2008.
71 - Mercier F, Kwon YC, Douet V. Hippocampus/amygdalaalterations, loss of heparan sulfates, fractones and ventricle Wall reduction in adult BTBR T+tf/J mice, animal model for autism. Neurosci Lett, 2012; 506:208–213.
72 - Klempin F, Beis D, Mosienko V, Kempermann G, Bader M, Alenina N. Serotonin is required for exercise-induced adult hippocampal neurogenesis. J Neurosci, 2013; 33:8270–8275.
73 - Anderson BM, Schnetz-Boutaud NC, Bartlett J, Wotawa AM, Wright HH, Abramson RK et al. Examination of association of genes in the serotonin system to autism. Neurogene, 2009; 10(3): 209-16.
74 - Cook EH Jr, Charak DA, Arida J, Spohn JA, Roizen NJ, Leventhal BL. Depressive and obsessive-compulsive symptoms in hyperserotonemic parents of children with autistic disorder. Psychiatry Res, 1994; 52: 25–33.
75 - Tordjman S, Anderson GM, Cohen D, Kermarrec S, Carlier M, Touitou Y, et al. Presence ofautism, hyperserotonemia, and severe expressive language impairment inWilliams-Beuren syndrome. Mol. Autism, 2013; 4:29.
76 - Daniels JL, Forssen U, Hultman CM, Cnattingius S, Savitz DA, Feychting M et al. Parental psychiatric disorders associated with autism spectrum disorders in the offspring. Pediatrics, 2008; 121:1357–62
77 - McDougle JC, Naylor TS, Cohen JD, Aghajanian KG, Heninger RG, Price HL. Effects of tryptophan depletion in drug-free adults with autistic disorder Arch Gen Psychiatry, 1996; 53: 993–1000.
78 - D’Eufemia P, Finochiaro R, Celli M, Viozzi L, Montelenone D, Giardini O. Low serum tryptophan to large neutral amino acids ratio in idiopathic infantile autism. Biomed Pharmacother, 1995; 49: 288–92.
79 - Croonenberghs J, Verkerk R, Scharpe S, Deboutte D, Maes M. Serotonergic disturbances in autistic disorder: L-5-hydroxytryptophan administration to autistic youngsters increases the blood concentrations of serotonin in patients but not in controls. Life Sci, 2005; 76: 2171–83
80 - Hollander E, Anagnostou E, Chaplin W, Esposito K, Haznedar MM, Licalzi E et al. Striatal volume on magnetic resonance imaging and repetitive behaviors in autism. Biol Psychiatry, 2005; 58: 226–232
81 - Nabi R, Serajee FJ, Chugani DC, Zhong H, Huq AH. Association of tryptophan 2,3 dioxygenase gene polymorphism with autism. Am J Med Genet, 2004; 125B:63–68.
82 - Lidow MS, Goldman-Rakic PS, Rakic P. Synchronized overproduction of neurotransmitter receptors in diverse regions of the primate cerebral cortex. Proc Natl Acad Sci USA, 1991; 88(22): 10218–10221.
83 - Biegon A, Greuner N. Age-related changes in serotonin 5HT2 receptors on human blood platelets. Psychopharmacology (Berl), 1992;108: 210–212.
84 - Chugani DC.Role of altered brain serotonin mechanisms in autism. Mol Psychiatry, 2002; 7(Suppl 2): 16 –17.
85 - Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J et al. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol, 1999; 45: 287–295
86 - Luo X, Persico A, Lauder J. Serotonergic regulation of somatosensory cortical development: Lessons from genetic mouse models. Dev Neurosci, 2003; 25: 173–183.
87 - Azmitia EC, Singh JS, Whitaker-Azmitia PM. Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autismdonors. Neuropharmacol, 2011; 60:1347–1354.
88 - Hadjikhani N. Serotonin, pregnancy and increased autism prevalence: is there a link? Med Hypotheses, 2010; 74:880–883.
89 - Nakamura K, Sekine Y, Ouchi Y, Tsujii M, Yoshikawa E, Futatsubashi M et al. Brain serotonin and dopamine transporter bindings in adults with high functioning autism. Arch Gen Psychiatry, 2010; 67,:59–68.
90 - Makkonen I, Riikonen R, Kokki H, Airaksinen MM, Kuikka JT. Serotonin and dopamine transporter binding in children with autism determined by SPECT. Dev Med Child Neurol, 2008; 50: 593–7.
91 - Connors SL, Matteson KJ, Sega GA, Lozzio CB, Carroll RC, Zimmerman AW. Plasma serotonin in autism. Pediatr Neurol. 2006; 35:182–186
92 - Boccuto L, Chen C-F, Pittman AR, Skinner CD, McCartney HJ, Jones K et al. Decreased tryptophan metabolism in patients with autism spectrum disorders. Mol Autism, 2013; 4:16.
93 - Carlsson ML, Martin P, Nilsson M, Sorensen SM, Carlsson A, Waters S et al.The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist than dopamine agonist–induced hyperactivity in mice. J Neural Transm,1999; 106: 123–129.
94 - McDougle CJ, Posey D. Genetics of childhood disorders: XLIV. Autism, part 3: Psychopharmacology of autism. J Am Acad Child Adolesc Psychiatry, 2002; 41: 1380 –1383.
95 - Lake CR, Ziegler MG, Murphy DL. Increased norepinephrine levels and decreased dopamine –beta-hydroxilase activity in primary autism. Arch Gen Psychiatry, 1997; 34: 553-556.
96 - Martineau J, Herault J, Petit E, Guerin P, Hameury L, Perrot A et al. Catecholaminergic metabolism and autism. Dev Med Child Neurol, 1994; 36(8): 688-97.
97 - Gillberg C, Svennerholm L. CSF monoamines in autistic syndromes and other pervasive developmental disorders of early childhood. Br J Psychiatry, 1987; 151: 89-94.
98 - Ernst M, Zametkin AJ, Matochik JA, Pascualvaca D, Cohen RM. Low medial prefrontal dopaminergic activity in autistic children. Lancet, 1997; 350: 638.
99 - Kaluzna-Czaplinska J, Socha E, Rynkowski J. Determination of homovanillic acid and vanillylmandelic acid in urine of autistic children by gas chromatography/mass spectrometry. Med. Sci. Monit. 2010, 16, CR445–CR450
100 - Robinson PD, Schutz CK, Macciardi F, White BN, Holden JJ. Genetically determined low maternal serum dopamine beta hydroxilase levels and the etiology of autism spectrum disorders. Am J Med Genet, 2001; 100: 30-36.
101 - Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012; 485(7397):242–245.
102 - Arehart-Treichel J. Nicotinic receptors may play role in development of autism. Psychiatric News, 2001; 36(14):19.
103 - Perry EK, Lee ML, Martin-Ruiz CM, Court JA, Volsen SG, Merrit J et al. Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain. Am J Psychiatry, 2001; 158: 1058-1066.
104 - Lee M, Martin-Ruiz C, Graham A, Court J, Jaros E, Perry R et al. Nicotinic receptor abnormalities in the cerebellar cortex in autism. Brain, 2002; 125:1483-1495
105 - Martin-Ruiz CM, Lee M, Perry RH, Baumann JA, Court JA, Perry EK. Molecular analysis of nicotinic receptor expression in autism. Mol Brain Res 2004;123:81–90.
106 - Ray MA, Graham AJ, Lee M, Perry RH, Court JA, Perry EK. Neuronal nicotinic acetylcholine receptor subunits in autism: an immunohistochemical investigation in the thalamus. Neurobiol Dis 2005;19:366–77.
107 - Yasui DH, Scoles HA, Horike S, Meguro-Horike M, Dunaway KW, Schroeder DI, Lasalle JM (2011) 15q11.2-13.3 chromatin analysis reveals epigenetic regulation of CHRNA7 with deficiencies in Rett and autism brain. Hum Mol Genet 20:4311–4323.