Memory Synapses Are Defined by Distinct Molecular Complexes: A Proposal

Abstract

Synapses are diverse in form and function. While there are strong evidential and theoretical reasons for believing that memories are stored at synapses, the concept of a specialized "memory synapse" is rarely discussed. Here, we review the evidence that memories are stored at the synapse and consider the opposing possibilities. We argue that if memories are stored in an active fashion at synapses, then these memory synapses must have distinct molecular complexes that distinguish them from other synapses. In particular, examples from Aplysia sensory-motor neuron synapses and synapses on defined engram neurons in rodent models are discussed. Specific hypotheses for molecular complexes that define memory synapses are presented, including persistently active kinases, transmitter receptor complexes and trans-synaptic adhesion proteins.

Keywords: AMPA receptors; Aplysia; engram cells; engram neuron; protein kinase M (PKM); synapse diversity; synapse formation; synaptic tagging and capture hypothesis.

Figure 1

Generating memory synapses. A set of neurons is presented with distributed basal synapses between presynaptic and postsynaptic pairs. An initial learning stimulus will (1) Allocate the memory to engram neurons (red somas); (2) Convert basal synapses between engram neurons to memory synapses with increased synaptic strength; and (3) Generate new synapses, both to neurons previously connected by synapses and neurons not connected. A repetition of the same learning stimulus can convert the new synapses into memory synapses between engram neurons, but new synapses between other neurons decay. However, a similar stimulus that is now paired with a different experience can lead to (1) Generation of new engram neurons; (2) the erasure of previous memory synapses, and (3) the conversion of new synapses between the old engram and new engram neuron into memory synapses.

Figure 2

A memory module at a synapse. The molecular memory complex is portrayed as a module with basal synaptic complexes at one synaptic connection. The molecular memory complex has memory-specific synaptic adhesion proteins, AMPA receptor complexes and presynaptic complexes. A persistent protein kinase is continually phosphorylating an endocytic adaptor protein preventing endocytosis of the molecular memory complex. Inactivation of the persistent protein kinase leads to endocytosis of the molecular memory complex in both the presynaptic and postsynaptic neuron.