Translational Control Mechanisms in Long-lasting Synaptic Plasticity and Memory

Abstract

Mnemonic processes are controlled by selective modification (weakening or strengthening) of connections between neurons (1,–5). To understand the precise molecular mechanisms by which this remarkably complex network encodes a given episode during learning is arguably one of the major challenges in modern neuroscience (6). Two kinds of memory storage mechanisms have been described: short-term memory (STM),3 which lasts only a few minutes or hours, and long-term memory (LTM), which persists for many weeks, months, years, and even a lifetime (7). Consolidation of LTM depends on de novo synthesis. Indeed, the first molecular distinction between STM and LTM emerged from studies with protein synthesis inhibitors >40 years ago: animals that were treated with drugs that block protein synthesis could not form LTM, yet their STM was preserved. More than a century ago, Dr. Santiago Ramon y Cajal, the great Spanish neuroanatomist, proposed that forming memories requires neurons to strengthen their connections with one another. Now, it is widely accepted that information is stored in the brain as changes in the strength of synaptic connections. Like LTM, long-lasting (but not short-lasting) changes in the strength of synaptic connections depend on new protein synthesis. Such changes can be observed when neuronal activity is recorded in brain slices with microelectrodes in vitro. Synaptic plasticity refers to the ability of the synapse to strengthen or weaken in response to experience. The best studied forms of synaptic plasticity are long-term potentiation (LTP) and long-term depression (LTD), which refer to facilitation and depression of synaptic strength, respectively (8). LTP can be divided into two distinct temporal phases: early LTP (E-LTP), which depends on modification of pre-existing proteins, is usually induced by one tetanic train, and lasts 1–2 h, and late LTP (L-LTP), which requires new protein synthesis, is induced by repetitive tetanic trains, and lasts for several hours (9). There is emerging evidence that local protein synthesis at dendrites could play a key role in long-lasting forms of synaptic plasticity (10). Recent genetic and molecular studies have cast new light on the molecular mechanisms underlying protein synthesis-dependent synaptic plasticity and memory storage. We discuss here some of the molecular mechanisms by which translational control regulates changes in synaptic strength and memory storage.