Still looking for the memories: Molecules and synaptic plasticity

Abstract

Computational neuroscientists have been playing around with plastic synapses for several decades. Interestingly, mechanistically detailed models of synaptic plasticity started around the same time as the CNS meetings. This was when the associative properties of the N-methyl-D-aspartate (NMDA) receptor were demonstrated, first setting out the molecular and mechanistic underpinnings of synaptic plasticity. Some 20 years ago there was little reason to expect that the underlying biology would turn out to be as outrageously complicated as we now find it. Associativity seemed to be established by the NMDA receptor especially through the work of Collingridge, and there were already a couple of candidate mechanisms for how to maintain synaptic weights: The CaMKII autocatalytic process found by several people and first modeled by Lisman, and the PKA story from Kandel. These leads led into a maze. Even 10 years ago, there were over a 100 known molecules implicated in synaptic plasticity. The first major molecular models of synaptic plasticity had some dozen signaling pathways-a far cry from what was known. The field as a whole is still playing catch-up. Nevertheless, most of the key properties of plasticity have had a good share of models, at various levels of detail. I suggest that there has been a recent shift in perspective, from enumerating molecules to looking at functional roles that may involve different, often overlapping sets of molecules. It is the identification and integration of these diverse functions of the synapse that is the key conceptual direction of the field. This has combined with technical and data- driven advances in managing and modeling multiscale phenomena spanning singlemolecule reaction-diffusion, through chemistry, electrical and structural effects, and the network. As many of us felt, 20 years ago, we are again at a fascinating time where the experiments, the databases, and the computational tools are just coming together to address these questions.