No evidence for a protein-synthesis-dependent form of long-term fear memory: Translational inhibition and neural inactivation disrupt short- and long-term memory measures to the same degree.

Translational inhibition has been suggested to impair long-term memory (LTM) while leaving short-term memory (STM) unaffected. However, intracranial infusions of protein synthesis inhibitors such as anisomycin (ANI), cycloheximide, and emetine have been shown to profoundly suppress both spontaneous and evoked neural activity, likely due to impairments of mitochondrial function and cellular metabolic loss. Given this neural suppressive effect, we wanted to re-examine the influence of translational inhibition on acquiring and retaining novel information with a direct comparison to agents that simply inactivate neural activity (without affecting protein synthesis). Our model was the widely-used cued-fear conditioning paradigm which is known to be dependent on the basolateral amygdala complex (BLA). Using male rats, we compared the behavioral deficits in cue fear conditioning induced by intra-BLA infusions of ANI to other commonly used neural inactivators, including the GABAA agonist muscimol (MUSC) and the sodium channel blocker tetrodotoxin (TTX). We confirmed that intra-BLA infusions of ANI and MUSC suppressed neural activity by examining effects on spiking activity in the BLA. In behavioral experiments, pre-training bilateral BLA infusions of ANI impaired both short-term (2 h) and long-term (24 h) cue fear memory similarly to the effects observed with both MUSC and TTX. Our results suggest that reductions in neural activity, whether via GABAA agonism, sodium channel blockade, or translational inhibition, are essential for both short- and long-term memory. Consequently, the influence of translational inhibitors may be better understood as being mediated via neural inactivation rather than solely the result of the absence of de novo synthesis of plasticity-related proteins. Previous work that interprets results using translational inhibitors as being purely protein-synthesis-dependent must to be reconsidered. SIGNIFICANCE STATEMENT: The axiomatic idea that protein synthesis can distinguish between phases of memory, namely short- versus long-term forms, is entirely based on work purporting to show differential disruptive effects of translational inhibitors on retrieval tested at long, but not short-term delays. However, protein synthesis inhibitors profoundly suppress neural activity as well, which should have an equivalent detrimental effect on both short- and long-term memory. In this study, we demonstrate that the translational inhibitor anisomycin suppresses neural activity in the basolateral amygdala which results in deficits in both short- and long-term memory for conditioned fear, similarly to agents that ONLY block neural activity. These findings are consistent with an important and under-appreciated role of neural activity in memory processes and argue for a critical re-evaluation of the strict de novo protein hypothesis of memory consolidation.