Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala

Abstract

Histone acetylation is a fundamental epigenetic mechanism that is dynamically regulated during memory formation. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) compete to modulate histone acetylation, allowing for rapid changes in acetylation in response to a learning event. HDACs are known to be powerful negative regulators of memory formation, but it is not clear whether this function depends on HDAC enzymatic activity per se. Here, we tested whether the enzymatic activity of an individual Class I HDAC, HDAC3, has a role in fear memory formation in subregions of the hippocampus and amygdala. We found that fear conditioning drove expression of the immediate early genes cFos and Nr4a2 in the hippocampus, which coincided with reduced HDAC3 occupancy at these promoters. Using a dominant-negative, deacetylase-dead point mutant virus (AAV-HDAC3(Y298H)-v5), we found that selectively blocking HDAC3 deacetylase activity in either the dorsal hippocampus or basal nucleus of the amygdala enhanced context fear without affecting tone fear. Blocking HDAC3 activity in the lateral nucleus of the amygdala, on the other hand, enhanced tone, but not context fear memory. These results show for the first time that the enzymatic activity of HDAC3 functions to negatively regulate fear memory formation. Further, HDAC3 activity regulates different aspects of fear memory in the basal and lateral subregions of the amygdala. Thus, the deacetylase activity of HDAC3 is a powerful negative regulator of fear memory formation in multiple subregions of the fear circuit.

Distinct roles for the deacetylase domain of HDAC3 in the hippocampus and medial prefrontal cortex in the formation and extinction of memory

“…Replacing a histidine for a tyrosine (Y298H) abolishes the enzymatic activity of HDAC3 (Kwapis et al, 2017; Lahm et al, 2007, Sun et al, 2013). We also added a V5 epitope tag to measure immunoreactivity and quantify viral mRNA expression of the HDAC3 point mutant independently of endogenous HDAC3 (Fig.…”

“…Animals were injected with either AAV-HDAC3(Y298H)-v5 or AAV-EV (Empty Vector) (Kwapis et al, 2017). For the DH experiments, 1 µlof virus was infused bilaterally.…”

“…Until recently, the deacetylase activity of HDAC3 in memory formation had not been directly tested. Kwapis and colleagues (2017) demonstrated that indeed the enzymatic activity of HDAC3 is required for amygdala-dependent forms of memory formation.…”

“…Histone acetylation is carried out by histone acetyltransferases and histone deacetylases (HDACs), which in general facilitate and repress gene expression, respectively (Jenuwein and Allis 2001; Kouzarides, 2007). Histone deacetylase 3 (HDAC3) is the most highly expressed Class I HDAC in the brain, and this specific HDAC is a powerful negative regulator of learning and memory processes (Kwapis et al, 2017; Malvaez et al, 2013; McQuown et al, 2011; Rogge et al, 2013). Our laboratory has shown that HDAC3 plays a critical role in object location and fear related memory formation (McQuown et al, 2011; Kwapis et al, 2017) using hippocampus and amygdala specific HDAC3 manipulations.…”

“…Histone deacetylase 3 (HDAC3) is the most highly expressed Class I HDAC in the brain, and this specific HDAC is a powerful negative regulator of learning and memory processes (Kwapis et al, 2017; Malvaez et al, 2013; McQuown et al, 2011; Rogge et al, 2013). Our laboratory has shown that HDAC3 plays a critical role in object location and fear related memory formation (McQuown et al, 2011; Kwapis et al, 2017) using hippocampus and amygdala specific HDAC3 manipulations. We have also shown that HDAC3 inhibition facilitates extinction of drug-seeking behavior in a manner that blocks reinstatement (Malvaez et al, 2013).…”