Synaptic plasticity and memory Both LTP and LTD are cellular mechanisms for learning10,11 and there are pronounced parallels between LTP and memory formation and storage. Both have two mechanistically distinct phases, which take place on very similar

time scales. The induction phase of LTP, in which synaptic function is initially enhanced, lasts under an hour. There is then a subsequent maintenance phase, in which the increased synaptic strength is fully Inhibitors,research,lifescience,medical established. In memory formation there is also an early phase, corresponding to initial learning, and a mechanistically distinguishable late phase, which CX-5461 mw corresponds to memory consolidation. The induction phase of LTP and the initial learning process in memory both occur without synthesis of new proteins, relying on post-transiational modifications of proteins already present Inhibitors,research,lifescience,medical at sites of potentiation.12 Since these changes are not permanent, and proteins have a limited half-life before they are degraded, the maintenance and consolidation phases of LTP

Inhibitors,research,lifescience,medical and memory therefore both require de novo protein synthesis.13 Mechanisms of plasticity The most widely studied forms of plasticity are induced by activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors (NMDARs) and expressed by changes in the number of postsynaptic AMPA receptors (AMPARs).14,15 NMDARs are nonspecific cation channels with a high permeability to Ca2+. Under normal resting membrane potential, however,

the channel is blocked Inhibitors,research,lifescience,medical by Mg2+ ions and this block is released by membrane depolarization.16,17 This property makes NMDARs coincidence detectors since they require both presynaptic glutamate release and postsynaptic depolarization Inhibitors,research,lifescience,medical for activation. The entry of Ca2+ and Na+ ions through the activated NMDAR leads to further depolarization, and when the local intracellular Ca2+ concentration reaches a threshold, signal transduction pathways are initiated that ultimately lead to changes in synaptic Dichloromethane dehalogenase responsiveness. Different patterns of NMDAR activity and spatiotemporal calcium dynamics elicit LTP or LTD. In electrophysiology experiments a train of electrical pulses is generally used to depolarize the neuron with high stimulus frequency to induce a rapid Ca2+ influx for LTP and lower frequency for LTD.18 Strong stimulation of afferent presynaptic neurons in hippocampal slices such as trains of 4 x 100 Hz stimulation with a 200-ms interval between θ bursts causes a rapid and substantial Ca2+ influx at the postsynapse which initiates LTP. This is believed to resemble the physiological activity that takes place in the brain during learning processes.19 In dispersed cultured neurons, it is possible to invoke LTP via activation of synaptic NMDARs with the coagonist, glycine.