Synaptic plasticity involves several processes by which the brain undergoes neural changes. Plasticity is usually dependent on glutamatergic synapses. Through these changes the efficacy of a particular synapse can increase or decrease depending on the particular change. The efficacy of a synapse can be changed by increasing or decreasing the amount of neurotransmitter presynaptically released across the synapse or by increasing or decreasing the amount of AMPA receptors present postsynaptically (thereby making that synapse more sensitive). Furthermore, the changes which occur at one synapse effects the entire network of neurons to which that synapse is connected. Two of these mechanisms which commonly affect the way efficacy of a synapse are Long Term Potentiation (LTP) and Long Term Depression (LTD).
Long Term Potentiation
This diagram outlines the mechanism of LTP. In LTP the AMPA receptors become sufficiently excited which leads to an influx of Na+ which leads to a dramatic depolarization of the postsynaptic cell (Excitatory Post Synaptic Potential EPSP). This EPSP releases the Magnesium ion blocking the NMDA receptor, and allows a Calcium-glutamate molecule to enter the cell. As intracellular [Ca] increases protein kinases such as calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) are activated. The activation of these two proteins allows for the 2 major mechanisms of LTP to proceed. These two mechanism are the phosphorylation of existing AMPA receptors (AMPAr's) thereby increasing their sensitivity, and the increase of postsynaptic AMPAr's due to kinase activity. In the late phase of LTP the synaptic changes that began in the early phase are continued, and are dependent on gene expression and protein synthesis. Late phase LTP is induced when sustained activation of the early phase kinases (CaMKII and PKC) activate the extracellular signal-regulated kinase (ERK). These kinases phosphorylate signal and nuclear proteins which in turn lead to protein synthesis, morphological changes of the neuron, and gene expression. Late phase LTP changes include both postsynaptic changes as well as presynaptic changes due to retrograde signaling. Postsynaptic changes include increased dendritic area and spines which increase postsynaptic sensitivity, and an increase in AMPA receptors inserted in the postsynaptic membrane.
Presynaptic changes are based on retrograde signaling and include an increase in presynaptic synaptotagmin (which aids in the binding and release of neurotransmitter vesicles from the presynaptic membrane) and an increase in the total number of presynaptic neurotransmitter vesicles.
These changes that occur in both the presynaptic and postsynaptic neurons are the underlying mechanisms for learning and addiction.
Long Term Depression
Long term depression (LTD) is also dependent on biochemical cascades within the neuron. In opposition to potentiation, depression decreases the efficacy of a synapse It has been observed in the cerebellum (possibly involved in motor learning), the hippocampus (possibly involved in memory decay), the visual cortex, and the prefrontal cortex. Generally the mechanism (displayed below) proceeds due to low frequency stimuli and a slow rise in postsynaptic [Ca]. In the hippocampus (displayed in diagram) [Ca] below threshold level leads to an activation of phosphatases which dephosphorylate AMPAr's causing them to be internalized, thereby causing the total sensitivity of the synapse to decrease. In the cerebellum LTD leads to a phosphorylation of AMPAr's which in turn leads to an internalization of AMPAr's which decreases the total efficacy of the synapse.