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Ability of a synapse to strengthen or weaken over time according to its activity
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. 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). Plastic change often results from the alteration of the number of neurotransmitter receptors located on a synapse. 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. Synaptic plasticity in both excitatory and inhibitory synapses has been found to be dependent upon postsynaptic calcium release. 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. The second mechanism depends on a second messenger cascade regulating gene transcription and changes in the levels of key proteins at pommel synapses 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. 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. 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. The end result is long term maintenance of LTP. The number of ion channels on the post synaptic membrane affects the strength of the synapse. 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. These processes, and by extension the number of receptors on the membrane, can be altered by synaptic activity. 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. 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. 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. Synaptic scaling is a primary mechanism by which a neuron to be selective to its varying inputs. 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. 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. Specificity is also an important aspect of CAMKII signaling involving nanodomain calcium.

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.

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. Depending on the time scales over which it acts synaptic enhancement is classified as neural facilitation, synaptic augmentation or post tetanic potentiation.

Synaptic fatigue or 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. heterosynaptic depression is thought to be linked to the release of adenosine triphosphate (ATP) from astrocytes.

Long term depression (LTD) and long term potentiation (LTP) are two forms of long term plasticity, lasting minutes or more, that occur at excitatory synapses. Recently, a number of attempts have been made to offer a comprehensive model that could account for most forms of synaptic plasticity.

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 serine release by astrocytes has been found to lead to a significant reduction of LTD in the hippocampus In the brain, cerebellum is one of the structures where LTD is a form of neuroplasticity.

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 as axonal bouton, dendritic spine and postsynaptic density. 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.

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. 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.