Wikipedia

Synaptic plasticity

This article is about synaptic plasticity. For the role of synapse formation and stabilization in plasticity, seeSynaptic stabilization.For the general concept of brain plasticity, seeneuroplasticityandSynaptic stabilization.

Inneuroscience,synaptic plasticityis the ability ofsynapsestostrengthen or weakenover time, in response to increases or decreases in their activity.[1]Sincememoriesare postulated to be represented by vastly interconnectedneural circuitsin thebrain,synaptic plasticity is one of the important neurochemical foundations oflearningandmemory(seeHebbian theory).

Synaptic plasticity rule for gradient estimation by dynamic perturbation of conductances

Plastic change often results from the alteration of the number ofneurotransmitter receptorslocated on a synapse.[2]There are several underlying mechanisms that cooperate to achieve synaptic plasticity, including changes in the quantity ofneurotransmittersreleased into a synapse and changes in how effectively cells respond to those neurotransmitters.[3]Synaptic plasticity in bothexcitatoryandinhibitorysynapses has been found to be dependent uponpostsynapticcalciumrelease.[2]

Historical discoveries

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In 1973,Terje LømoandTim Blissfirst described the now widely studied phenomenon oflong-term potentiation(LTP) in a publication in theJournal of Physiology.The experiment described was conducted on the synapse between theperforant pathanddentate gyrusin thehippocampiof anaesthetised rabbits. They were able to show a burst of tetanic (100 Hz) stimulus on perforant path fibres led to a dramatic and long-lasting augmentation in the post-synaptic response of cells onto which these fibres synapse in the dentate gyrus. In the same year, the pair published very similar data recorded from awake rabbits. This discovery was of particular interest due to the proposed role of the hippocampus in certain forms of memory.

Biochemical mechanisms

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Two molecular mechanisms for synaptic plasticity involve theNMDAandAMPAglutamate receptors. Opening of NMDA channels (which relates to the level of cellulardepolarization) leads to a rise in post-synaptic Ca2+concentration and this has been linked to long-term potentiation, LTP (as well as to proteinkinaseactivation); strong depolarization of the post-synaptic cell completely displaces themagnesiumions that block NMDA ion channels and allows calcium ions to enter a cell – probably causing LTP, while weaker depolarization only partially displaces the Mg2+ions, resulting in less Ca2+entering the post-synaptic neuron and lower intracellular Ca2+concentrations (which activate protein phosphatases and inducelong-term depression,LTD).[4]

These activated protein kinases serve to phosphorylate post-synaptic excitatory receptors (e.g.AMPA receptors), improving cation conduction, and thereby potentiating the synapse. Also, these signals recruit additional receptors into the post-synaptic membrane, stimulating the production of a modified receptor type, thereby facilitating an influx of calcium. This in turn increases post-synaptic excitation by a given pre-synaptic stimulus. This process can be reversed via the activity of protein phosphatases, which act to dephosphorylate these cation channels.[5]

The second mechanism depends on asecond messengercascade regulatinggene transcriptionand changes in the levels of key proteins such asCaMKIIand PKAII. Activation of the second messenger pathway leads to increased levels of CaMKII and PKAII within thedendritic spine.These protein kinases have been linked to growth in dendritic spine volume and LTP processes such as the addition of AMPA receptors to theplasma membraneand phosphorylation of ion channels for enhanced permeability.[6]Localization or compartmentalization of activated proteins occurs in the presence of their given stimulus which creates local effects in the dendritic spine. Calcium influx from NMDA receptors is necessary for the activation of CaMKII. This activation is localized to spines with focal stimulation and is inactivated before spreading to adjacent spines or the shaft, indicating an important mechanism of LTP in that particular changes in protein activation can be localized or compartmentalized to enhance the responsivity of single dendritic spines. Individual dendritic spines are capable of forming unique responses to presynaptic cells.[7]This second mechanism can be triggered byprotein phosphorylationbut takes longer and lasts longer, providing the mechanism for long-lasting memory storage. The duration of the LTP can be regulated by breakdown of thesesecond messengers.Phosphodiesterase,for example, breaks down the secondary messengercAMP,which has been implicated in increased AMPA receptor synthesis in the post-synaptic neuron[citation needed].

Long-lasting changes in the efficacy of synaptic connections (long-term potentiation,or LTP) between two neurons can involve the making and breaking of synaptic contacts. Genes such as activin ß-A, which encodes a subunit ofactivin A,are up-regulated during early stage LTP. The activin molecule modulates the actin dynamics in dendritic spines through theMAP-kinase pathway.By changing theF-actincytoskeletalstructure of dendritic spines, spine necks are lengthened producing increased electrical isolation.[8]The end result is long-term maintenance of LTP.[9]

The number ofion channelson the post-synaptic membrane affects the strength of the synapse.[10]Research suggests that the density of receptors on post-synaptic membranes changes, affecting the neuron's excitability in response to stimuli. In a dynamic process that is maintained in equilibrium,N-methyl D-aspartate receptor (NMDA receptor)and AMPA receptors are added to the membrane byexocytosisand removed byendocytosis.[11][12][13]These processes, and by extension the number of receptors on the membrane, can be altered by synaptic activity.[11][13]Experiments have shown that AMPA receptors are delivered to the synapse through vesicularmembrane fusionwith the postsynaptic membrane via the protein kinase CaMKII, which is activated by the influx of calcium through NMDA receptors. CaMKII also improves AMPA ionic conductance through phosphorylation.[14] When there is high-frequency NMDA receptor activation, there is an increase in the expression of a proteinPSD-95that increases synaptic capacity for AMPA receptors.[15]This is what leads to a long-term increase in AMPA receptors and thus synaptic strength and plasticity.

If the strength of a synapse is only reinforced by stimulation or weakened by its lack, apositive feedback loopwill develop, causing some cells never to fire and some to fire too much. But two regulatory forms of plasticity, called scaling andmetaplasticity,also exist to providenegative feedback.[13]Synaptic scaling is a primary mechanism by which a neuron is able to stabilize firing rates up or down.[16]

Synaptic scalingserves to maintain the strengths of synapses relative to each other, lowering amplitudes of smallexcitatory postsynaptic potentialsin response to continual excitation and raising them after prolonged blockage or inhibition.[13]This effect occurs gradually over hours or days, by changing the numbers ofNMDA receptorsat the synapse (Pérez-Otaño and Ehlers, 2005).Metaplasticityvaries the threshold level at which plasticity occurs, allowing integrated responses to synaptic activity spaced over time and preventing saturated states of LTP and LTD. Since LTP and LTD (long-term depression) rely on the influx ofCa2+through NMDA channels, metaplasticity may be due to changes in NMDA receptors, altered calcium buffering, altered states of kinases or phosphatases and a priming of protein synthesis machinery.[17]Synaptic scaling is a primary mechanism by which a neuron to be selective to its varying inputs.[18] The neuronal circuitry affected by LTP/LTD and modified by scaling and metaplasticity leads to reverberatory neural circuit development and regulation in a Hebbian manner which is manifested as memory, whereas the changes in neural circuitry, which begin at the level of the synapse, are an integral part in the ability of an organism to learn.[19]

There is also a specificity element of biochemical interactions to create synaptic plasticity, namely the importance of location. Processes occur at microdomains – such asexocytosisof AMPA receptors is spatially regulated by thet-SNARESTX4.[20]Specificity is also an important aspect of CAMKII signaling involving nanodomain calcium.[7] The spatial gradient of PKA between dendritic spines and shafts is also important for the strength and regulation of synaptic plasticity.[6]It is important to remember that the biochemical mechanisms altering synaptic plasticity occur at the level of individual synapses of a neuron. Since the biochemical mechanisms are confined to these "microdomains," the resulting synaptic plasticity affects only the specific synapse at which it took place.

Theoretical mechanisms

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A bidirectional model, describing both LTP and LTD, of synaptic plasticity has proved necessary for a number of different learning mechanisms incomputational neuroscience,neural networks,andbiophysics.Three major hypotheses for the molecular nature of this plasticity have been well-studied, and none are required to be the exclusive mechanism:

  1. Change in the probability of glutamate release.
  2. Insertion or removal of post-synaptic AMPA receptors.
  3. Phosphorylationand de-phosphorylation inducing a change in AMPA receptor conductance.

Of these, the latter two hypotheses have been recently mathematically examined to have identical calcium-dependent dynamics which provides strong theoretical evidence for a calcium-based model of plasticity, which in a linear model where the total number of receptors are conserved looks like

where

  • is thesynaptic weightof theth input axon,
  • is the concentration of calcium,
  • is a time constant dependent on the insertion and removal rates of neurotransmitter receptors, which is dependent on,and
  • is also a function of the concentration of calcium that depends linearly on the number of receptors on the membrane of the neuron at some fixed point.

Bothandare found experimentally and agree on results from both hypotheses. The model makes important simplifications that make it unsuited for actual experimental predictions, but provides a significant basis for the hypothesis of a calcium-based synaptic plasticity dependence.[21]

Short-term plasticity

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Short-term synaptic plasticity acts on a timescale of tens of milliseconds to a few minutes unlike long-term plasticity, which lasts from minutes to hours. Short-term plasticity can either strengthen or weaken a synapse.

Synaptic enhancement

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Short-term synaptic enhancement results from an increased probability of synaptic terminals releasing transmitters in response to pre-synaptic action potentials. Synapses will strengthen for a short time because of an increase in the amount of packaged transmitter released in response to each action potential.[22]Depending on the time scales over which it acts synaptic enhancement is classified asneural facilitation,synaptic augmentationorpost-tetanic potentiation.

Synaptic depression

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Synaptic fatigueor depression is usually attributed to the depletion of the readily releasable vesicles. Depression can also arise from post-synaptic processes and from feedback activation of presynaptic receptors.[23] heterosynapticdepression is thought to be linked to the release ofadenosine triphosphate(ATP) fromastrocytes.[24]

Long-term plasticity

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Long-term depression(LTD) andlong-term potentiation(LTP) are two forms of long-term plasticity, lasting minutes or more, that occur at excitatory synapses.[2]NMDA-dependent LTD and LTP have been extensively researched, and are found to require the binding ofglutamate,andglycineorD-serinefor activation of NMDA receptors.[24] The turning point for the synaptic modification of a synapse has been found to be modifiable itself, depending on the history of the synapse.[25]Recently, a number of attempts have been made to offer a comprehensive model that could account for most forms of synaptic plasticity.[26]

Long-term depression

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Brief activation of an excitatory pathway can produce what is known as long-term depression (LTD) of synaptic transmission in many areas of the brain. LTD is induced by a minimum level of postsynaptic depolarization and simultaneous increase in the intracellular calcium concentration at the postsynaptic neuron. LTD can be initiated at inactive synapses if the calcium concentration is raised to the minimum required level by heterosynaptic activation, or if the extracellular concentration is raised. These alternative conditions capable of causing LTD differ from the Hebb rule, and instead depend on synaptic activity modifications.D-serinerelease byastrocyteshas been found to lead to a significant reduction of LTD in the hippocampus.[24] Activity-dependent LTD was investigated in 2011 for the electrical synapses (modification of Gap Junctions efficacy through their activity).[27]In the brain, cerebellum is one of the structures where LTD is a form of neuroplasticity.[28]

Long-term potentiation

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Long-term potentiation, commonly referred to as LTP, is an increase in synaptic response following potentiating pulses of electrical stimuli that sustains at a level above the baseline response for hours or longer. LTP involves interactions between postsynaptic neurons and the specific presynaptic inputs that form a synaptic association, and is specific to the stimulated pathway of synaptic transmission. The long-term stabilization of synaptic changes is determined by a parallel increase of pre- and postsynaptic structures such asaxonal bouton,dendritic spineandpostsynaptic density.[15] On the molecular level, an increase of the postsynaptic scaffolding proteinsPSD-95andHomer1chas been shown to correlate with the stabilization of synaptic enlargement.[15]

Modification of astrocyte coverage at the synapses in the hippocampus has been found to result from theinduction of LTP,which has been found to be linked to the release ofD-serine,nitric oxide,and thechemokine,s100Bbyastrocytes.[24] LTP is also a model for studying the synaptic basis of Hebbian plasticity. Induction conditions resemble those described for the initiation of long-term depression (LTD), but a stronger depolarization and a greater increase of calcium are necessary to achieve LTP.[29]Experiments performed by stimulating an array of individual dendritic spines, have shown that synaptic cooperativity by as few as two adjacent dendritic spines prevents LTD, allowing only LTP.[30]

Synaptic strength

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The modification ofsynaptic strengthis referred to as functional plasticity. Changes in synaptic strength involve distinct mechanisms of particular types ofglial cells,the most researched type beingastrocytes.[24]

Computational use of plasticity

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Every kind of synaptic plasticity has different computational uses.[31] Short-term facilitation has been demonstrated to serve as both working memory and mapping input for readout, short-term depression for removing auto-correlation. Long-term potentiation is used for spatial memory storage while long-term depression for both encoding space features, selective weakening of synapses and clearing old memory traces respectively. Forwardspike-timing-dependent plasticityis used for long range temporal correlation, temporal coding and spatiotemporal coding. The reversedspike-timing-dependent plasticityacts as sensory filtering.

See also

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References

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