The Lysine Acetyltransferase PCAF Functionally Interacts with Estrogen Receptor Alpha in the Hippocampus of Gonadally Intact Male - but not Female - Rats to Enhance Short-term Memory

Acetylation of histone proteins by histone acetyltransferases (HATs), and the resultant change in gene expression, is a well-established mechanism necessary for long-term memory (LTM) consolidation, which is not required for short-term memory (STM). However, we previously demonstrated that the HAT p300/CBP-associated factor (PCAF) also influences hippocampus (HPC)-dependent STM in male rats. In addition to their epigenetic activity, HATs acetylate non-histone proteins involved in non-genomic cellular processes, such as estrogen receptors (ERs). Given that ERs have rapid, non-genomic effects on HPC-dependent STM, we investigated the potential interaction between ERs and PCAF for STM mediated by the dorsal HPC (dHPC). Using a series of pharmacological agents administered directly into the dHPC, we reveal a functional interaction between PCAF and ERα in the facilitation of short-term object-in-place memory in male but not female rats. This interaction was specific to ERα, while ERβ agonism did not enhance STM. It was further specific to dHPC STM, as the effect was not present in the dHPC for LTM or in the perirhinal cortex. Additional experiments indicated that while STM required local (i.e., dHPC) estrogen synthesis, the facilitatory interaction effect might be independent of estrogens. Finally, western blot analyses demonstrated that PCAF activation in the dHPC rapidly (5min) activated downstream estrogen-related cell signaling kinases (c-Jun N-terminal kinase and extracellular signal-related kinase). Collectively, these findings indicate that PCAF, which is typically implicated in LTM through epigenetic processes, also influences STM in the dHPC, possibly via non-genomic ER activity. Critically, this novel PCAF-ER interaction might exist as a male-specific mechanism supporting STM.Significance Statement Due to their ability to modulate gene expression, epigenetic mechanisms are necessary for long-term, but not short-term, memory. Recently, the histone acetyltransferase PCAF, has been shown to be necessary in the hippocampus for short-term object memory, but its mechanism of action is unknown. Here, we present evidence for a novel functional interaction between PCAF and estrogen receptors (ERs) in the hippocampus of gonadally-intact male - but not female - rats that enhanced short-term object memory. Further, enhancing PCAF led to rapid activation of downstream ER-related signaling cascades, suggesting that PCAF might activate ERs similar to the effects of estrogens. Indeed, experiments suggested that the PCAF-ER interaction could be estrogen-independent. These results demonstrate a novel mechanism mediating short-term memory enhancement that appears to be specific to males.