Chapter 1 Introductory Chapter : Mechanisms and Function of Synaptic Plasticity

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 changes­can­manifest­themselves­in­altering­both­the­structure­and­function­of­neural­­circuits.­ Neural circuits are built by neurons, which form points of contacts with each other, the synapses [1].­A­given­neuron­can­ form­thousands­of­ synapses­on­ its­dendrites,­ cell­body­and­ 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 modification­of­synaptic­transmission­termed­synaptic­plasticity­(reviewed­in­[2]).­Below,­a­ description of synaptic plasticity is provided in terms of its historical context, mechanisms of its­different­forms,­and­directions­of­research­on­synaptic­plasticity.


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 changescanmanifestthemselvesinalteringboththestructureandfunctionofneural 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 modificationofsynaptictransmissiontermedsynapticplasticity(reviewedin [2]).Below,a description of synaptic plasticity is provided in terms of its historical context, mechanisms of itsdifferentforms,anddirectionsofresearchonsynapticplasticity.

A brief history of synaptic plasticity
Thetermplasticityhasitsorigininsciencemorethan100yearsagoandhasbeenattributedto 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,RamónyCajaldiscoveredthatneuronsareunique 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].
Theideaandconceptofsynapticplasticitygainedprominenceinthelate1940swithpioneering 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,theyareplastic.Mammalianbrainsareremarkablyplastic,whichimpliesanability to modify existing neural circuits and to alter future behavior, emotions, and responses to sensory input [12].Synapticplasticityreferstoactivity-dependentchangesintheefficacyof 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 memoriesthatcanlastformanyyears.

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 neurotransmittersreleasedfromthepresynapticneuronintoasynapse,or(c)inreceptorsensitivitytothereleasedneurotransmitters [26][27][28][29].Synapticplasticityhasbeenfoundatsynapses thatconveyglutamate-mediatedexcitationandatothersynapsesthatmediateGABAergicinhibition [2,30].Synapticplasticitytakesplaceatdifferenttimescales,fromtensofmilliseconds tolife-longchangesinsynaptictransmission.Therefore,synapticplasticitycanbeclassifiedas eithershort-termorlong-term.Short-termsynapticplasticityoccursattimeperiodsfromsubsecondtominuteswhereaslong-termsynapticplasticitychangestheefficacyofsynapsesfor hourstoyearsandisthoughttoformlastingmemoriesthatarestoredinbraincircuits.
Thetermsneuroplasticity,neuralplasticity,orbrainplasticityareusedinabroadercontextto indicate changes that occur throughout a person's life either at the synapse or whole neurons orevenentirebrainregions.Thebasicpremiseisthesame,namelythatcertainaspectsofthe brain or brain function can be changed throughout life [31].Thiswasnotalwaysunderstood tobethecase.Previousstudiesofthebrainsuggestedtheexistenceofacriticalperiodearly inlifeduringwhichthebrainisamenabletochangesofstructureandfunction(plastic)and wouldremainunchangeablethereafter(static)(reviewedin [30,32]).Likewise,synapseswere considered as simple relay stations for information transfer from one neuron to another or fromaneurontoamusclecell.Theserelaystationswerethoughttobeestablishedduring developmentandtoremaininplacethroughoutlifewitharelativelyfixedsynapticstrength 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].

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'sexperiences.Plasticitymanifestsitselfasdynamicshiftsinthestrengthofpreexisting connectionsacrossdistributedneuralnetworksandasmodificationsofthemappingbetween behaviorandneuralactivitythattakeplaceinresponsetochangesinafferentinputorefferent demand [32].Notonlycanexistingconnectionsundergorapidchanges,theestablishmentof new connections through dendritic growth and arborization can follow [33][34][35][36].Synapticand/ 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 becomecentraltoourunderstandingofthemechanismsoflearningandmemory.Synaptic plasticity is intimately related to learning and memory because memories are thought to be representedbyneuralnetworksthatareconnectedatsynapses.Onecriticalconceptinthis regard is the Hebbian theory [11], which proposes an explanation for neuronal adaptation duringthelearningprocessandisconsideredabasicmechanismforsynapticplasticity.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 stimulatesapostsynapticneuron,i.e.,whenbothneuronsareactive,synapticconnectionsare modifiableintheirefficacy.Hebb'stheoryhasbeensummarizedinamorecolloquialwayby SiegridLöwel'sphrase:"Cellsthatfiretogether,wiretogether [37]."Oneimportantaspect of Hebb's theory relates to the exact timing of activity of the presynaptic neuron in relation to postsynapticactivity.Thepresynapticcellneedstogenerateactionpotentialsjustbefore the postsynaptic cell and not at the same time, a concept known as spike-timing-dependent plasticity [38].
Itisnowgenerallyacceptedthatmemoriesarestoredasalterationsinthestrengthofsynaptic connections between neurons [30].Alterationsinsynapticefficacyhavebeentracedforhours tomonths,andtherefore,LTPisboththemostwidelystudiedandthemostpopularcandidate cellular mechanism for storing information in neural circuits over long-time periods. IrrespectiveoftheusefulnessofLTPandLTDasexamplesoflong-lastingsynapticplasticity, someauthorshavecautionedthatitisnotclearhowLTPandLTDrelatetomemory,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].

Developments and directions of synaptic plasticity research
Synaptic plasticity has become an overriding theme of brain research in order to understand thenervoussysteminitsfunctionanddysfunction.Overthepastseveraldecades,researchers haveattemptedandsucceededindecipheringmolecularandcellularsynapticchangesthat are the basis for behavior and disease [75][76][77].However,eventhoughourunderstandingof synaptic plasticity has grown tremendously, pivotal questions regarding plasticity and its functionremaintothisday,e.g.,howdothedifferentformsofsynapticplasticitycompliment or interfere with each other [55,78].