Synapses and memory storage

Abstract

The synapse is the functional unit of the brain. During the last several decades we have acquired a great deal of information on its structure, molecular components, and physiological function. It is clear that synapses are morphologically and molecularly diverse and that this diversity is recruited to different functions. One of the most intriguing findings is that the size of the synaptic response in not invariant, but can be altered by a variety of homo- and heterosynaptic factors such as past patterns of use or modulatory neurotransmitters. Perhaps the most difficult challenge in neuroscience is to design experiments that reveal how these basic building blocks of the brain are put together and how they are regulated to mediate the information flow through neural circuits that is necessary to produce complex behaviors and store memories. In this review we will focus on studies that attempt to uncover the role of synaptic plasticity in the regulation of whole-animal behavior by learning and memory.

Figure 1.

Short-term and long-term sensitization of the gill-withdrawal refex in Aplysia involves posttranslational modifications and alterations in protein synthesis. (Left) The gill-withdrawal circuit. A tactile stimulus to the siphon causes a sensory neuron to release glutamate to excite a motor neuron. (Center) A shock to the tail causes serotonin release from interneurons. This activates a stimulatory G protein (G), which activates adenylyl cyclase (AC), leading to production of cAMP and PKA-dependent phosphorylation of different substrates, including K⁺ and Ca²⁺ channels, which enhances glutamate release from the sensory neuron terminals. (Right) Repeated shocks to the tail elicit a persistent increase in cAMP, leading to altered gene transcription and protein synthesis. This leads to growth of new synapses.

Figure 2.

Multiple forms of long-term synaptic plasticity may contribute to learning and memory. (Top) A single train of high-frequency tetanic synaptic stimulation can produce forms of long-term potentiation (LTP) of synaptic transmission lasting 1–2 h. This early LTP (E-LTP) does not require changes in transcription or translation. Different patterns of tetanic stimulation can recruit distinct forms of E-LTP that differ in molecular mechanism and site of expression. Multiple trains of tetanic synaptic stimulation can induce a more persistent form of synaptic plasticity that can persist for many hours. This late LTP (L-LTP) requires altered gene expression, activation of PKA, and new protein synthesis. (Bottom) Weaker forms of synaptic activity can lead to a long-term depression of synaptic transmission (LTD). Different patterns of synaptic stimulation recruit distinct forms of LTD through differing signaling pathways.

Figure 3.

Molecular mechanisms for induction of LTP and memory. These basic signaling pathways have been implicated in both NMDAR-dependent LTP and behavioral learning. Short-term plasticity (lasting several hours) is produced by NMDAR-dependent Ca²⁺ signaling to protein kinases and the recruitment of new glutamate receptors to the synapse. Long-term plasticity (lasting days) requires CREB-dependent gene activation in the nucleus by the action of multiple protein kinases. Long-term plasticity and memory also requires synthesis of a constitutively active isoform of PKC.