Synaptic plasticity

In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity.^[1] Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory (see Hebbian theory).

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

Plastic change often results from the alteration of the number of neurotransmitter receptors located on a synapse.^[2] There are several underlying mechanisms that cooperate to achieve synaptic plasticity, including changes in the quantity of neurotransmitters released into a synapse and changes in how effectively cells respond to those neurotransmitters.^[3] Synaptic plasticity in both excitatory and inhibitory synapses has been found to be dependent upon postsynaptic calcium release.^[2]

Historical discoveries[edit]

In 1973, Terje Lømo and Tim Bliss first described the now widely studied phenomenon of long-term potentiation (LTP) in a publication in the Journal of Physiology. The experiment described was conducted on the synapse between the perforant path and dentate gyrus in the hippocampi of 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[edit]

Two molecular mechanisms for synaptic plasticity involve the NMDA and AMPA glutamate receptors. Opening of NMDA channels (which relates to the level of cellular depolarization) leads to a rise in post-synaptic Ca²⁺ concentration and this has been linked to long-term potentiation, LTP (as well as to protein kinase activation); strong depolarization of the post-synaptic cell completely displaces the magnesium ions 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 induce long-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 a second messenger cascade regulating gene transcription and changes in the levels of key proteins such as CaMKII and PKAII. Activation of the second messenger pathway leads to increased levels of CaMKII and PKAII within the dendritic spine. These protein kinases have been linked to growth in dendritic spine volume and LTP processes such as the addition of AMPA receptors to the plasma membrane and 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 by protein phosphorylation but takes longer and lasts longer, providing the mechanism for long-lasting memory storage. The duration of the LTP can be regulated by breakdown of these second messengers. Phosphodiesterase, for example, breaks down the secondary messenger cAMP, which has been implicated in increased AMPA receptor synthesis in the post-synaptic neuron .

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 of activin A, are up-regulated during early stage LTP. The activin molecule modulates the actin dynamics in dendritic spines through the MAP-kinase pathway. By changing the F-actin cytoskeletal structure of dendritic spines, spine necks are lengthened producing increased electrical isolation.^[8] The end result is long-term maintenance of LTP.^[9]

The number of ion channels on 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 by exocytosis and removed by endocytosis.^[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 vesicular membrane fusion with 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 protein PSD-95 that 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, a positive feedback loop will develop, causing some cells never to fire and some to fire too much. But two regulatory forms of plasticity, called scaling and metaplasticity, also exist to provide negative feedback.^[13] Synaptic scaling is a primary mechanism by which a neuron is able to stabilize firing rates up or down.^[16]

Synaptic scaling serves to maintain the strengths of synapses relative to each other, lowering amplitudes of small excitatory postsynaptic potentials in 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 of NMDA receptors at the synapse (Pérez-Otaño and Ehlers, 2005). Metaplasticity varies 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 of Ca²⁺ 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 as exocytosis of AMPA receptors is spatially regulated by the t-SNARE STX4.^[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.

$W_{i}$ is the of the $i$ th input axon,

synaptic weight

$[Ca^{2+}]$ is the concentration of calcium,

$\tau$ is a time constant dependent on the insertion and removal rates of neurotransmitter receptors, which is dependent on $[Ca^{2+}]$ , and

$\Omega =\beta A_{m}^{\rm {fp}}$ 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.

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

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

Both $\Omega$ and $\tau$ are 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]

Synaptic strength[edit]

The modification of synaptic strength is referred to as functional plasticity. Changes in synaptic strength involve distinct mechanisms of particular types of glial cells, the most researched type being astrocytes.^[24]

Computational use of plasticity[edit]

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. Forward spike-timing-dependent plasticity is used for long range temporal correlation, temporal coding and spatiotemporal coding. The reversed spike-timing-dependent plasticity acts as sensory filtering.

Archived 2017-05-02 at the Wayback Machine

Overview

Finnerty lab, MRC Centre for Neurodegeneration Research, London

Brain Basics Synaptic Plasticity Synaptic transmission is plastic

Neuroscience Online (electronic neuroscience textbook by UT Houston Medical School)