Synaptic Dialogue: Substrate for Protein-Synthesis-Independent Long-Term Memory

Abstract

The present article makes three points concerning the mechanism of long-lasting memory. First, such a mechanism requires 'synaptic dialogue', a term coined by Colley and Routtenberg (1993) to describe a model of ongoing, self-regenerating, autocatalytic, bi-directional communication between the two sides of the synapse (see Figure 1). Inherent in this model is an intrinsic positive feedback system providing the capacity to maintain the newly altered 'state of the synapse' for long periods of time. Because it is a positive feedback system, it is essential to incorporate well-known regulatory mechanisms, such as protein phosphatases and proteases intercellularly and synaptic inhibition intracellularly to prevent runaway activity. Second, the 'state of the synapse' is the sum of the regulated post-translational modifications (PTMs) of proteins already present at the synapse. PTMs vary considerably at the mechanistic level as they may involve, but are not limited to, protein phosphorylation, proteolysis, protein translocation or a polymerization reaction. Here we will focus on the protein phosphorylation mechanism with a further focus on protein kinase C (PKC) phosphorylation of preor postsynaptic substrates. The concatenation of these PTMs in each of the synaptic compartments represents the signaling system that is orchestrated to maintain the altered synaptic state. Third, the maintenance of long-lasting synaptic change does not require de novo protein synthesis as an instructive mechanism. The main event that prolongs synaptic change is the PTM of proteins already present at the preand post-synaptic sides. Protein synthesis serves to replenish these modified proteins but it is the PTM of synaptic proteins that serves the main instructive event for long-term memory storage. A critical analysis of the de novo protein synthesis model for long-term memory storage has recently been completed (Routtenberg and Rekart, 2005) and so will not be discussed further here.