InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Neuroscience » "Synaptic Plasticity", book edited by Thomas Heinbockel, ISBN 978-953-51-3234-9, Print ISBN 978-953-51-3233-2, Published: June 21, 2017 under CC BY 3.0 license. © The Author(s).

Chapter 1

Introductory Chapter: Mechanisms and Function of Synaptic Plasticity

By Thomas Heinbockel
DOI: 10.5772/67891

Article top

Introductory Chapter: Mechanisms and Function of Synaptic Plasticity

Thomas Heinbockel
Show details

1. Introduction

Many everyday experiences such as reading a book like this one, classroom learning, drug taking, or stressful situations can result in changes of our brain at different levels. These changes can manifest themselves in altering both the structure and function of neural circuits. Neural circuits are built by neurons, which form points of contacts with each other, the synapses [1]. A given neuron can form thousands of synapses on its dendrites, cell body and axon, and through synaptic transmission, communicates information with other neurons in the nervous system. It is at the synapses that changes in brain function occur through modification of synaptic transmission termed synaptic plasticity (reviewed in [2]). Below, a description of synaptic plasticity is provided in terms of its historical context, mechanisms of its different forms, and directions of research on synaptic plasticity.

2. A brief history of synaptic plasticity

The term plasticity has its origin in science more than 100 years ago and has been attributed to the famous Spanish scientist and founder of modern neuroscience Santiago Ramón y Cajal [3, 4]. His idea that the brain can store information by modifying synaptic connections was expressed in 1894 [5], even 3 years before Charles Sherrington introduced the term synapse for connections between neurons [6, 7]. Subsequently, Ramón y Cajal discovered that neurons are unique entities and synapses are the points of communication between them, the neuron doctrine [8]. It was also Ramón y Cajal who insisted that small spiny protrusions of dendrites, dendritic spines, were not an artifact but real and that they have a key role in mediating synaptic connectivity [9].

The idea and concept of synaptic plasticity gained prominence in the late 1940s with pioneering work by the Polish neurophysiologist Konorski [10] and the Canadian psychologist Hebb [11]. Konorski described plasticity as “permanent functional transformations,” and Hebb attributed testable physiologic characteristics to synaptic plasticity [6]. Synaptic plasticity means that the connections between nerve cells in the brain are not static but can undergo changes, they are plastic. Mammalian brains are remarkably plastic, which implies an ability to modify existing neural circuits and to alter future behavior, emotions, and responses to sensory input [12]. Synaptic plasticity refers to activity-dependent changes in the efficacy of synaptic communication and has been proposed to be critically involved in the remarkable capacity of the brain to translate transient experiences into apparently unlimited numbers of memories that can last for many years.

Even though the notion of synaptic plasticity dates back to the end of the nineteenth century, it took almost 80 years before experimental evidence was obtained to demonstrate that synapses are capable of long-lasting changes in synaptic strength [13]. Timothy Bliss and Terry Lomo experimentally induced an increase in the synaptic strength of neurons in the mammalian hippocampus as a result of electrical stimulation. Such an increase in postsynaptic responses is now called long-term potentiation (LTP). Further experimentation by Serena Dudek and Mark Bear [14] revealed the ability of synapses to change in two directions, namely to increase (LTP) or decrease (long-term depression, LTD) in strength, i.e., synapses undergo activity-driven bidirectional modification. Both LTP and LTD have been found in various brain regions, most prominently the hippocampus [2, 15], cerebellum [16], cerebral cortex [1719], and the amygdala [2025] where sensory input has been linked to motor output in fear conditioning paradigms.

3. Synaptic and neural plasticity

Principally, synaptic plasticity refers to the strengthening or weakening of synaptic contacts as a result of increasing or decreasing activity levels of the neurons involved in a particular neural circuit. Synaptic plasticity implies direct regulation of pre- and/or postsynaptic neurons through alterations of the synaptic machinery. Examples include changes (a) of the number of neurotransmitter receptors in the postsynaptic membrane, (b) in the quantity of neurotransmitters released from the presynaptic neuron into a synapse, or (c) in receptor sensitivity to the released neurotransmitters [2629]. Synaptic plasticity has been found at synapses that convey glutamate-mediated excitation and at other synapses that mediate GABAergic inhibition [230]. Synaptic plasticity takes place at different time scales, from tens of milliseconds to life-long changes in synaptic transmission. Therefore, synaptic plasticity can be classified as either short-term or long-term. Short-term synaptic plasticity occurs at time periods from subsecond to minutes whereas long-term synaptic plasticity changes the efficacy of synapses for hours to years and is thought to form lasting memories that are stored in brain circuits.

The terms neuroplasticity, neural plasticity, or brain plasticity are used in a broader context to indicate changes that occur throughout a person’s life either at the synapse or whole neurons or even entire brain regions. The basic premise is the same, namely that certain aspects of the brain or brain function can be changed throughout life [31]. This was not always understood to be the case. Previous studies of the brain suggested the existence of a critical period early in life during which the brain is amenable to changes of structure and function (plastic) and would remain unchangeable thereafter (static) (reviewed in [30, 32]). Likewise, synapses were considered as simple relay stations for information transfer from one neuron to another or from a neuron to a muscle cell. These relay stations were thought to be established during development and to remain in place throughout life with a relatively fixed synaptic strength of the connection. Neuroscience textbooks nowadays appreciate the extreme plasticity of most synapses such that they are able to change their strength as a result of either their own activity or through activity in another pathway [30].

4. Plasticity, memory, and learning

Plasticity is now known to be an intrinsic property of the brain such that it is not limited by its own genome but can adapt to external stressors, physiological alterations, and a person’s experiences. Plasticity manifests itself as dynamic shifts in the strength of preexisting connections across distributed neural networks and as modifications of the mapping between behavior and neural activity that take place in response to changes in afferent input or efferent demand [32]. Not only can existing connections undergo rapid changes, the establishment of new connections through dendritic growth and arborization can follow [3336]. Synaptic and/or neural plasticity is the mechanism for development and learning, but it is also the basis of much brain pathology as seen in various neurological disorders, and maladaptive synaptic plasticity may contribute to neuropsychiatric disorders [2].

While synaptic plasticity is a key concept in itself for brain function and dysfunction, it has become central to our understanding of the mechanisms of learning and memory. Synaptic plasticity is intimately related to learning and memory because memories are thought to be represented by neural networks that are connected at synapses. One critical concept in this regard is the Hebbian theory [11], which proposes an explanation for neuronal adaptation during the learning process and is considered a basic mechanism for synaptic plasticity. Hebb postulated that coincident activity of synaptically connected neurons leads to lasting changes in the efficacy of synaptic transmission. Experimental evidence supports this hypothesis by demonstrating that modifiable synapses exist in brain and form the basis for learning and memory. Under conditions when a presynaptic neuron repeatedly and persistently stimulates a postsynaptic neuron, i.e., when both neurons are active, synaptic connections are modifiable in their efficacy. Hebb’s theory has been summarized in a more colloquial way by Siegrid Löwel’s phrase: “Cells that fire together, wire together [37].” One important aspect of Hebb’s theory relates to the exact timing of activity of the presynaptic neuron in relation to postsynaptic activity. The presynaptic cell needs to generate action potentials just before the postsynaptic cell and not at the same time, a concept known as spike-timing-dependent plasticity [38].

It is now generally accepted that memories are stored as alterations in the strength of synaptic connections between neurons [30]. Alterations in synaptic efficacy have been traced for hours to months, and therefore, LTP is both the most widely studied and the most popular candidate cellular mechanism for storing information in neural circuits over long-time periods. Irrespective of the usefulness of LTP and LTD as examples of long-lasting synaptic plasticity, some authors have cautioned that it is not clear how LTP and LTD relate to memory, i.e., the causal link between LTP and memory has not been demonstrated convincingly (reviewed in Ref. [30]), especially for hippocampal LTP. Other forms of memory and plasticity have allowed linking cellular events and circuitry to behavior, e.g., classical conditioning in the invertebrate model Aplysia, eye-blink conditioning, and amygdala-dependent fear conditioning [30, 39, 40]. Particularly, cerebellar LTD and amygdalar LTP are considered to directly underlie memory-associated behavioral changes [41, 42].

5. Endocannabinoids as mediators of synaptic plasticity

Over the past two decades, a new set of signaling molecules has been implicated in synaptic plasticity, namely, endogenously generated cannabinoids, the endocannabinoids (eCBs) [2, 4354]. Two endocannabinoids, N-arachidonoylethanol-amide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) have been found to be the natural agonists of cannabinoid receptors in the brain, CB1R [46]. These signaling molecules are unusual neurotransmitters because they are not stored in synaptic vesicles in synaptic terminals. Instead, endocannabinoids are made on-demand from membrane lipids of activated neurons and are released nonsynaptically. Nevertheless, they have been shown to be involved in synaptic plasticity in many neural systems in both short-term and long-term plasticity, learning and memory such as extinction of aversive memories [5256]. Endocannabinoids are known to play a role in synapse formation, neurogenesis, and a number of bodily functions such feeding [57, 58], anxiety, pain reception, and recovery after brain injury [5962]. Endocannabinoids serve as intercellular messengers in the brain [46]. They act in a retrograde fashion at synapses and presynaptically regulate both glutamatergic and GABAergic synapses to alter release-probability in synaptic plasticity. Endocannabinoids mediate short-term synaptic plasticity through a form of neuronal communication known as DSI, Depolarization-induced Suppression of Inhibition (reviewed in [46, 53, 54]). During DSI, when a principal neuron is activated through experimental current injection or activation of metabotropic glutamate or acetylcholine receptors, the inhibitory input onto that principal neuron is transiently reduced or abolished. When a postsynaptic principal neuron experiences a brief increase in intracellular calcium concentration, it synthesizes and releases endocannabinoids that travel to the presynaptic neuron and bind to cannabinoid receptors triggering an intracellular messenger cascade. The result is a transient decline of incoming inhibitory signals in the form of GABA arriving from presynaptic neurons. During DSI, endocannabinoids travel from the postsynaptic cell to the presynaptic GABA-releasing one and through activation of CB1R turn off neurotransmitter release. Endocannabinoids, thereby, act as retrograde-signaling molecules. DSI works as a transient local effect because endocannabinoids are lipids that cannot diffuse widely in the extracellular watery space of neurons. DSI allows neurons to disconnect briefly from other neurons or alter the strength of synapses made onto them through relieve of their inhibition [46]. DSI is a regulatory process allowing neurons to control their own synaptic excitability in an activity-dependent manner. A corresponding form of short-term synaptic plasticity has been described in the cerebellum, DSE, Depolarization-induced Suppression of Excitation, which reduces synaptic excitation by suppressing presynaptic glutamate release [44].

In addition to serving a role in mediating short-term synaptic plasticity, endocannabinoids have been shown to be critical in several forms of long-term synaptic plasticity. In the hippocampus, endocannabinoids evoke long-term depression at inhibitory, but not excitatory, synapses [63]. Endocannabinoid-mediated LTD (eCB-LTD) was described in the cerebellum [64], in the glutamatergic synapses onto medium spiny neurons in the striatum [65, 66] and at synapses between layer V pyramidal neurons in the neocortex [67]. Here, eCB-LTD does not depend on postsynaptic activation of metabotropic glutamate receptors but requires coincident activation of presynaptic ionotropic glutamate (NMDA) receptors. eCB-LTD in both the dorsal and the ventral striatum with the nucleus accumbens requires postsynaptic activation of group I metabotropic glutamate receptors [2, 6870]. Differences exist regarding a requirement for concomitant presynaptic activity [71], the known involvement of anandamide as the endocannabinoid [72] and the presence of postsynaptic D2 dopamine receptors [73, 74] in the dorsal striatum.

6. Developments and directions of synaptic plasticity research

Synaptic plasticity has become an overriding theme of brain research in order to understand the nervous system in its function and dysfunction. Over the past several decades, researchers have attempted and succeeded in deciphering molecular and cellular synaptic changes that are the basis for behavior and disease [7577]. However, even though our understanding of synaptic plasticity has grown tremendously, pivotal questions regarding plasticity and its function remain to this day, e.g., how do the different forms of synaptic plasticity compliment or interfere with each other [55, 78].

Technical advances in neuroscience research are also a major catalyst for progress in synaptic plasticity research. Most recently, among these advances are genetic, optical, and optogenetic methods that allow researchers to manipulate single cells or neural circuits with subcellular precision, at microsecond timescales or through longitudinal electrophysiological and optical recordings [7989]. Novel experimental and conceptual approaches will pave the way to a more complete understanding of the functional consequences of synaptic plasticity and its implication for health and disease.


This work was supported in part by grants from the National Science Foundation (NSF IOS-1355034) and the Charles and Mary Latham Trust Fund.

Conflict of interest

The author declares that there is no conflict of interests regarding the publication of this chapter.


1 - Sheng M, Sabatini BL, Südhof TC. The Synapse. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press, 2012, 397 p.
2 - Citri A, Malenka RC. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology 2008; 33:18-41; doi:10.1038/sj.npp.1301559
3 - Jones EG. Plasticity and neuroplasticity. J History Neurosci 2000; 9:37-39.
4 - Jones EG. Plasticity and neuroplasticity. J History Neurosci 2004; 13:293.
5 - Ramón y Cajal S. La fine structure des centres nerveux. The Croonian lecture. Proc R Soc Lond B Biol Sci 1894; 55:443-468. doi:10.1098/rspl.1894.0063
6 - “Neuroplasticity.” Encyclopedia of Aging. (February 6, 2017).
7 - Sherrington CS. The Integrative Action of the Nervous System (1st ed.). Oxford University Press: H. Milford, 1906, pp. xvi, 411 p.
8 - Jones EG. Colgi, cajal and the neuron doctrine. J History Neurosci 1999; 8:170-178.
9 - Yuste R. The discovery of dendritic spines by Cajal. Front Neuroanat 2015; 9:18. doi: 10.3389/fnana.2015.00018 P MCID: PMC4404913
10 - Konorski J. Conditioned reflexes and neuron organization. Tr. from the Polish ms. under the author’s supervision. Cambridge University Press, New York, NY, US. xiv 267 pp., 1948.
11 - Hebb DO. The Organization of Behavior. New York: John Wiley, 1949.
12 - Malenka RC. Synaptic plasticity. In: Neuropsychopharmacology: The Fifth Generation of Progress. Editors: Davis KL, Charney D, Coyle JT, Nemeroff C; Philadelphia, Pennsylvania: Lippincott, Williams, & Wilkins, 2002, ch. 11, pp. 147-157
13 - Bliss TVP, Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol (London) 1973; 232: 331-356.
14 - Dudek SM, Bear MF. Homosynaptic long-term depression in area CA1 of hipocampus and effects of N-methyl-D-aspartate receptor blockade. Proceedings of the National Academy of Science 1992; 89:4363-4367.
15 - Bear MF, Abraham WC. Long-term depression in hippocampus. Annu Rev Neurosci 1996; 19:437-462.
16 - Linden DJ, Connor JA. Long-term synaptic depression. Annu Rev Neurosci 1995; 18:319 –357.
17 - Tsumoto T. Long-term potentiation and depression in the cerebral neocortex. Jpn J Physiol 1990; 40(5):573-593.
18 - Siegelbaum SA, Kandel ER. Learning-related synaptic plasticity: LTP and LTD. Curr Opin Neurobiol 1991; 1(1):113-120.
19 - Kullmann DM, Lamsa KP. LTP and LTD in cortical GABAergic interneurons: emerging rules and roles. Neuropharmacology 2011; 60(5):712-719. doi: 10.1016/j.neuropharm.2010.12.020
20 - Rogan MT, Staubli UV, LeDoux JE. Fear conditioning induces associative long-term potentiation in the amygdala. Nature 1997; 390:604-607.
21 - McKernan MG, Shinnick-Gallagher P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 1997; 390:607-611.
22 - Li H, Weiss SRB, Chuang D-M, Post RM, Rogawski MA. Bidirectional synaptic plasticity in the rat basolateral amygdala: characterization of an activity-dependent switch sensitive to the presynaptic metabotropic glutamate receptor antagonist 2S-a-ethylglutamic acid. J Neurosci 1998; 18:1662-1670.
23 - Heinbockel T, HC Pape. Input specific long term depression in the lateral amygdala evoked by theta-frequency stimulation. J Neurosci 2000; 20: RC68.
24 - Bauer EP, LeDoux JE, Nader K. Fear conditioning and LTP in the lateral amygdala are sensitive to the same stimulus contingencies. Nat Neurosci 2001; 4(7): 687-688.
25 - Pape HC, Driesang RB, Heinbockel T, Laxmi TR, Meis S, Seidenbecher T, Szinyei C, Frey U, Stork O. Cellular processes in the amygdala: gates to emotional memory? Zoology 2001; 104:232-240.
26 - Gaiarsa JL, Caillard O, Ben-Ari Y. Long-term plasticity at GABAergic and glycinergic synapses: mechanisms and functional significance. Trend Neurosci 2002; 25(11):564-570. doi:10.1016/S0166-2236(02)02269-5
27 - Lüscher C, Malenka RC. NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). In: Sheng M, Sabatini BL, Südhof TC (eds.), 2012: The Synapse. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press, pp. 251-265.
28 - Castillo PE. Presynaptic LTP and LTD of excitatory and inhibitory synapses. In: Sheng M, Sabatini BL, Südhof TC (eds.), 2012: The Synapse. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press, pp. 267-289.
29 - Mayford M, Siegelbaum SA, Kandel ER. Synapses and memory storage. In: Sheng M, Sabatini BL, Südhof TC (eds.), 2012: The Synapse. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press, pp. 331-348.
30 - Byrne JH, LaBar KS, LeDoux JE, Schafe GE, Sweatt JD, Thompson RF. Learning and memory: basic mechanisms. In: From Molecules to Networks, eds. Byrne JH, Roberts JL, 2nd ed, 2009, Oxford, UK: Academic Press, pp. 539-608.
31 - Rakic, P. Neurogenesis in adult primate neocortex: an evaluation of the evidence. Nature Rev Neurosci 2002; 3(1): 65-71. doi:10.1038/nrn700. PMID 11823806
32 - Pascual-Leone A, Amedi A, Fregni F, Merabet LB. The plastic human brain cortex. Annu Rev Neurosci 2005; 28: 377-401. doi:10.1146/annurev.neuro.27.070203.144216
33 - Engert F, Bonhoeffer T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 1999; 399(6731):66-70. PMID: 10331391
34 - Yuste R, Bonhoeffer T. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci 2001; 24:1071-1089. PMID: 11520928
35 - Nägerl UV, Eberhorn N, Cambridge SB, Bonhoeffer T. Bidirectional activity-dependent morphological plasticity in hippocampal neurons. Neuron 2004; 44(5):759-67. PMID: 15572108
36 - Hofer SB, Mrsic-Flogel TD, Bonhoeffer T, Hübener M. Experience leaves a lasting structural trace in cortical circuits. Nature 2009; 457(7227):313-317. doi: 10.1038/nature07487. PMID: 19005470
37 - Löwel S, Singer W. Selection of intrinsic horizontal connections in the visual cortex by correlated neuronal activity. Science 1992; 255:209-212.
38 - Caporale N, Dan Y. Spike timing-dependent plasticity: a Hebbian learning rule. Ann Rev Neurosci 2008; 31:25-46. doi: 10.1146/annurev.neuro.31.060407.125639. PMID 18275283
39 - Kim JJ, Thompson RF. Cerebellar circuits and synaptic mechanisms involved in classical eyeblink conditioning. Trends Neurosci 1997; 20:177-181.
40 - Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses. Science 2001; 294(5544):1030-1038.
41 - Lisberger SG. Cerebellar LTD: a molecular mechanism of behavioral learning? Cell 1998; 92(6):701-704.
42 - LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci 2000; 23:155-184.
43 - Wilson RI, Nicoll RA. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 2001; 410:588-592.
44 - Kreitzer AC, Regehr WG. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 2001; 29:717-727.
45 - Maejima T, Ohno-Shosaku T, Kano M. Endogenous cannabinoid as a retrograde messenger from depolarized postsynaptic neurons to presynaptic terminals. Neurosci Res 2001; 40:205-210.
46 - Alger BE. Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog Neurobiol 2002; 68:247-286.
47 - Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 2003; 83:1017-1066.
48 - Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 2004; 47:345-358.
49 - Chevaleyre V, Takahashi KA, Castillo PE. Endocannabinoid-mediated synaptic plasticity in the CNS. Annu Rev Neuroscience 2006; 29:37-76.
50 - Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 2009; 89:309-380.
51 - Cachope R. Functional diversity on synaptic plasticity mediated by endocannabinoids. Philos Trans R Soc Lond B Biol Sci 2012; 367:3242-3253
52 - Castillo PE, Younts TJ, Chávez AE, Hashimotodani Y. Endocannabinoid signaling and synaptic function. Neuron 2012; 76:70-81.
53 - Katona I, Freund TF. Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci. 2012; 35:529-558.
54 - Heinbockel T. Neurochemical communication: The case of endocannabinoids. In: Neurochemistry. Thomas Heinbockel (ed), ISBN 978-953-51-1237-2, Rijeka, Croatia: InTech Open Access Publisher, 2014, ch. 6, pp. 179-198.
55 - Alger BE. Endocannabinoids at the synapse a decade after the dies mirabilis (29 March 2001): what we still do not know. J Physiol 2012; 590.10:2203-2212.
56 - Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgansberger W, Di Marzo V, Lutz B. The endogenous cannabinoid system controls extinction of aversive memories. Nature 2002; 418:530-534.
57 - Cota D, Marsicano G, Lutz B, Vicennati V, Stalla GK, Pasquali R, Pagotto. Endogenous cannabinoid system as a modulator of food intake. Int J Obesity 2003; 27:289-301.
58 - Soria-Gómez E, Bellocchio L, Reguero L, Lepousez G, Martin C, Bendahmane M, Ruehle S, Remmers F, Desprez T, Matias I, Wiesner T, Cannich A, Nissant A, Wadleigh A, Pape HC, Chiarlone AP, Quarta C, Verrier D, Vincent P, Massa F, Lutz B, Guzmán M, Gurden H, Ferreira G, Lledo PM, Grandes P, Marsicano G. The endocannabinoid system controls food intake via olfactory processes. Nat Neurosci 2014; 17:407-415. doi: 10.1038/nn.3647.
59 - Iversen L, Chapman V. Cannabinoids: a real prospect for pain relief. Curr Opin Pharmacol 2002; 2:50-55.
60 - Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutierrez SO, van der Stelt M, Lopez-Rodriguez ML, Casanova E, Schutz G, Zieglgansberger W, Di Marzo V, Behl C, Lutz B. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 2003; 302:84-88.
61 - Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 2001; 413:527-531.
62 - Calignano A, Katona I, Desarnaud F, Giuffrida A, La Rana G, Mackie K, Freund TF, Piomelli D. Bidirectional control of airway responsiveness by endogenous cannabinoids. Nature 2000; 408:96-101.
63 - Chevaleyre V, Castillo PE. Endocannabinoid-mediated metaplasticity in the hippocampus. Neuron 2004; 43:871-881.
64 - Safo PK, Regehr WG. Endocannabinoids control the induction of cerebellar LTD. Neuron 2005; 48:647-659.
65 - Gerdeman GL, Ronesi J, Lovinger DM. Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat Neurosci 2002; 5:446-451.
66 - Robbe D, Alonso G, Chaumont S, Bockaert J, Manzoni OJ. Role of p/q-Ca2+ channels in metabotropic glutamate receptor 2/3-dependent presynaptic long-term depression at nucleus accumbens synapses. J Neurosci 2002; 22: 4346-4356.
67 - Sjostrom PJ, Turrigiano GG, Nelson SB. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron 2003; 39: 641-654.
68 - Sung KW, Choi S, Lovinger DM. Activation of group I mGluRs is necessary for induction of long-term depression at striatal synapses. J Neurophysiol 2001; 86:2405-2412.
69 - Kreitzer AC, Malenka RC. Dopamine modulation of state-dependent endocannabinoid release and long-term depression in the striatum. J Neurosci 2005; 25:10537-10545.
70 - Robbe D, Kopf M, Remaury A, Bockaert J, Manzoni OJ. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci USA 2002; 99:8384-8388.
71 - Singla S, Kreitzer AC, Malenka RC. Mechanisms for synapse specificity during striatal long-term depression. J Neurosci 2007; 27:5260-5264.
72 - Ade KK, Lovinger DM. Anandamide regulates postnatal development of long-term synaptic plasticity in the rat dorsolateral striatum. J Neurosci 2007; 27:2403-2409.
73 - Tang K, Low MJ, Grandy DK, Lovinger DM. Dopamine-dependent synaptic plasticity in striatum during in vivo development. Proc Natl Acad Sci USA 2001; 98:1255-1260.
74 - Kreitzer AC, Malenka RC. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models. Nature 2007; 445:643-647.
75 - Sweatt JD. Neural plasticity and behavior- sixty years of conceptual advances. J Neurochem 2016;139 Suppl 2:179-199. doi: 10.1111/jnc.13580.
76 - Cobar LF, Yuan L, Tashiro A. Place cells and long-term potentiation in the hippocampus. Neurobiol Learn Mem 2016; pii: S1074-7427(16)30274-X. doi: 10.1016/j.nlm.2016.10.010.
77 - Rayman JB, Kandel ER. Functional prions in the brain. Cold Spring Harb Perspect Biol 2017; 9(1). pii: a023671. doi: 10.1101/cshperspect.a023671.
78 - Turrigiano G. The dialectic of Hebb and homeostasis. Philos Trans R Soc Lond B Biol Sci 2017; 372(1715). pii: 20160258. doi: 10.1098/rstb.2016.0258.
79 - Heinbockel T, Brager DH, Reich C, Zhao J, Muralidharan S, Alger BE, Kao JPY. Endocannabinoid signaling dynamics probed with optical tools. J Neurosci 2005; 25: 9449-9459.
80 - Kao JPY. Controlling neurophysiology with light and caged molecules. In: Optical control of neural excitability. Keshishian H (ed), Washington, DC: Society for Neuroscience; 2008, pp. 1-12.
81 - Helmchen F, Konnerth A (eds.) Imaging in Neuroscience—A Laboratory Manual. Series Editor: Yuste R, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press, 2011, 1084 p.
82 - Heinbockel T. Electrophysiological recording and imaging of neuronal signals in brain slices. In: Neuroscience. Heinbockel T (ed.), Rijeka, Croatia: Intech, 2012, ch 2, pp. 19-48.
83 - Lerner TN, Ye L, Deisseroth K. Communication in neural circuits: tools, opportunities, and challenges. Cell 2016; 164(6):1136-1150. doi: 10.1016/j.cell.2016.02.027.
84 - Rajasethupathy P, Ferenczi E, Deisseroth K. Targeting neural circuits. Cell 2016; 165(3):524-534. doi: 10.1016/j.cell.2016.03.047.
85 - Yang MG, West AE. Editing the neuronal genome: a CRISPR view of chromatin regulation in neuronal development, function, and plasticity. Yale J Biol Med 2016; 89(4):457-470.
86 - Costa RP, Mizusaki BE, Sjöström PJ, van Rossum MC. Functional consequences of pre- and postsynaptic expression of synaptic plasticity. Philos Trans R Soc Lond B Biol Sci 2017; 372(1715). pii: 20160153. doi: 10.1098/rstb.2016.0153.
87 - Clopath C, Bonhoeffer T, Hübener M, Rose T. Variance and invariance of neuronal long-term representations. Philos Trans R Soc Lond B Biol Sci 2017; 372(1715). pii: 20160161. doi: 10.1098/rstb.2016.0161.
88 - Dehorter N, Marichal N, Marín O, Berninger B. Tuning neural circuits by turning the interneuron knob. Curr Opin Neurobiol 2017; 42:144-151. doi: 10.1016/j.conb.2016.12.009.
89 - Knafo S, Esteban JA. PTEN: local and global modulation of neuronal function in health and disease. Trends Neurosci 2017; 40(2):83-91. doi: 10.1016/j.tins.2016.11.008.