Silent Synapses in Cocaine-Associated Memory and Beyond

Abstract

Glutamatergic synapses are key cellular sites where cocaine experience creates memory traces that subsequently promote cocaine craving and seeking. In addition to making across-the-board synaptic adaptations, cocaine experience also generates a discrete population of new synapses that selectively encode cocaine memories. These new synapses are glutamatergic synapses that lack functionally stable AMPARs, often referred to as AMPAR-silent synapses or, simply, silent synapses. They are generatedde novoin the NAc by cocaine experience. After drug withdrawal, some of these synapses mature by recruiting AMPARs, contributing to the consolidation of cocaine-associated memory. After cue-induced retrieval of cocaine memories, matured silent synapses alternate between two dynamic states (AMPAR-absent vs AMPAR-containing) that correspond with the behavioral manifestations of destabilization and reconsolidation of these memories. Here, we review the molecular mechanisms underlying silent synapse dynamics during behavior, discuss their contributions to circuit remodeling, and analyze their role in cocaine-memory-driven behaviors. We also propose several mechanisms through which silent synapses can form neuronal ensembles as well as cross-region circuit engrams for cocaine-specific behaviors. These perspectives lead to our hypothesis that cocaine-generated silent synapses stand as a distinct set of synaptic substrates encoding key aspects of cocaine memory that drive cocaine relapse.

The ventral hippocampus and nucleus accumbens as neural substrates for cocaine contextual memory reconsolidation

“…Thus, it is possible to hypothesize based on the current findings and our previous work that cocaine memory reconsolidation involves activation of vHPC glutamatergic neurons projecting to the NA which stimulates NMDA receptors located on MSN and signaling through GSK3β and mTORC1 to produce changes in protein synthesis needed for long-term memory [49]. The literature supports glutamatergic synapses as key cellular sites where cocaine experience creates memory traces that can then promote cocaine craving and seeking, and that these synapses can be generated in the NA following cocaine experience [50].…”

Carbonic anhydrase 4 disruption decreases synaptic and behavioral adaptations induced by cocaine withdrawal

“…These withdrawal-associated changes in Car4 −/− mice suggest that CA4 disruption does not prevent all effects of cocaine withdrawal. In Car4 +/+ mice, the concomitant increase in both spine density and mEPSC frequency supports the likelihood that the number of functioning synapses is increased following withdrawal (28,40). However, in Car4 −/− mice, the withdrawal-associated spine changes without significant changes in mEPSC amplitude or frequency suggest that the spine changes are less likely to produce functional effects.…”

Studying Synaptic Connectivity and Strength with Optogenetics and Patch-Clamp Electrophysiology

“…This is especially the case since these may occur in the absence of AMPAR-mediated ones at so-called silent synapses, which can be created but also unsilenced by salient experiences. For instance, environmental stimuli such as addictive drugs [ 16 , 17 ] or stress [ 18 ] can ultimately drive AMPAR insertion in the postsynaptic membranes of previously silent synapses. In the absence of AMPAR responses it is therefore possible to miss (the potential for) ionotropic glutamatergic synaptic connectivity if NMDAR responses are not evaluated.…”