Synaptic plasticity and memory

The cellular basis of memory involves activity dependent plasticity in synaptic connections. An important model in the study of the cellular basis of memory is the phenomenon of long-term potentiation (LTP), a long-lasting increase in the strength of a synaptic response following stimulation (Bliss et al., 2007). LTP is prominent in the hippocampus, as well as in the cerebral cortex and other brain areas that are involved in different forms of memory. LTP is typically induced by the co-occurence of excitatory input and intracellular depolarization at the so-called Hebbian synapse, involving N-methyl-d-aspartate (NMDA) receptors that allow the entry of Ca++ into the synapse, which activates cyclic adenosine monophosphate (cAMP). Subsequently, cAMP activates several kinases, some of which increase the number of synaptic receptors. In addition, cAMP activates cAMP-response element binding protein (CREB), which operates within the nucleus to activate a class of genes called immediate early genes, which, in turn, activate other genes that direct protein synthesis. Among the proteins produced is neurotrophin, which activates growth of the synapse. Thus, a series of molecular reactions plays a vital role in fixating the changes in synaptic function that occur in LTP.

Evidence that the permanent fixation of memories depends on this molecular and cellular cascade of events comes from studies showing that memory fixation can be halted by interference with the molecules in this cascade. Many studies have shown that drugs that block NMDA receptors, cAMP, CREB, or other molecules involved in protein synthesis block memory. These treatments are effective when given before or within minutes after learning, and but are not effective if they are delayed, indicating that the molecular cascade leading to protein synthesis is not essential to initial learning or to maintaining short-term memory, but is essential for permanent memory fixation. In addition, studies using genetically modified mice have shown that alterations in specific genes for these molecules can dramatically affect the capacities for LTP and memory fixation.

In addition to LTP, there is also mechanism that diminishes the strength of connections at infrequently used synapses called long term depression (LTD). LTD involves the same molecular substrates as LTP but occurs with different timing rules of activity at synapses. The combination LTP and LTD allow for a sophisticated reorganization of circuits that create neural representations of information. LTP and LTD occur among all brain structures that are known to participate in different kinds of memory. These cellular and molecular events occur on a timescale of seconds and minutes, are essential for the transition from short-term storage to long-term memory, and occur in every brain structure that participates in memory.