Memory and the brain: unexpected chemistries and a new pharmacology

Efforts to characterize long-term potentiation (LTP) and to identify its substrates have led to the discovery of novel synaptic chemistries, computational algorithms, and, most recently, pharmacologies. Progress has also been made in using LTP to develop a "standard model" of how unusual, but physiologically plausible, levels of afferent activity create lasting changes in the operating characteristics of synapses in the cortical telencephalon. Hypotheses of this type typically distinguish induction, expression, and consolidation stages in the formation of LTP. Induction involves a sequence consisting of theta-type rhythmic activity, suppression of inhibitory currents, intense synaptic depolarization, NMDA receptor activation, and calcium influx into dendritic spines. Calcium-dependent lipases, kinases, and proteases have been implicated in LTP induction. Regarding the last group, it has been recently reported that theta pattern stimulation activates calpain and that translational suppression of the protease blocks potentiation. It is thus likely that proteolysis is readily driven by synaptic activity and contributes to structural reorganization. LTP does not interact with treatments that affect transmitter release, has a markedly differential effect on the currents mediated by colocalized AMPA vs NMDA synaptic receptors, changes the waveform of the synaptic current, modifies the effects of drugs that modulate AMPA receptors, and is sensitive to the subunit composition of those receptors. These results indicate that LTP is expressed by changes in AMPA receptor operations. LTP is accompanied by modifications in the anatomy of synapses and spines, something which accounts for its extreme duration (weeks). As with various types of memory, LTP requires about 30 min to consolidate (become resistant to disruption). Consolidation involves adhesion chemistries and, in particular, activation of integrins, a class of transmembrane receptors that control morphology in numerous cell types. Platelet activating factor and adenosine may contribute to consolidation by regulating the engagement of latent integrins. How consolidation stabilizes LTP expression is a topic of intense investigation but probably involves modifications to one or more of the following: membrane environment of AMPA receptors; access of regulatory proteins (e.g., kinases, proteases) to the receptors; receptor clustering; and space available for receptor insertion. Attempts to enhance LTP have focused on the induction phase and resulted in a class of centrally active drugs ("ampakines") that positively modulate AMPA receptors. These compounds promote LTP in vivo and improve the encoding of variety of memory types in animals. Positive results have also been obtained in preliminary studies with humans.