The Histone Deacetylase HDAC4 Regulates Long-Term Memory in Drosophila

Abstract

A growing body of research indicates that pharmacological inhibition of histone deacetylases (HDACs) correlates with enhancement of long-term memory and current research is concentrated on determining the roles that individual HDACs play in cognitive function. Here, we investigate the role of HDAC4 in long-term memory formation in Drosophila. We show that overexpression of HDAC4 in the adult mushroom body, an important structure for memory formation, resulted in a specific impairment in long-term courtship memory, but had no affect on short-term memory. Overexpression of an HDAC4 catalytic mutant also abolished LTM, suggesting a mode of action independent of catalytic activity. We found that overexpression of HDAC4 resulted in a redistribution of the transcription factor MEF2 from a relatively uniform distribution through the nucleus into punctate nuclear bodies, where it colocalized with HDAC4. As MEF2 has also been implicated in regulation of long-term memory, these data suggest that the repressive effects of HDAC4 on long-term memory may be through interaction with MEF2. In the same genetic background, we also found that RNAi-mediated knockdown of HDAC4 impairs long-term memory, therefore we demonstrate that HDAC4 is not only a repressor of long-term memory, but also modulates normal memory formation.

Long-Term Memory inDrosophilaIs Influenced by Histone Deacetylase HDAC4 Interacting with SUMO-Conjugating Enzyme Ubc9

“…The truncated form of HDAC4 also caused cognitive deficits in mice, which were associated with reduced expression of plasticity-related genes (Sando et al 2012). We also demonstrated that overexpression of HDAC4 in Drosophila resulted in impaired LTM and recruited MEF2 to discrete foci within nuclei (Fitzsimons et al 2013). Taken together, these data indicate that when in the nucleus, HDAC4 has the capacity to repress expression of plasticity-related genes, which correlates with memory impairment (Sando et al 2012); however, it also plays a promemory role, as evidenced by the memory impairments that result from reduction of HDAC4 in the adult brain Fitzsimons et al 2013).…”

“…We also demonstrated that overexpression of HDAC4 in Drosophila resulted in impaired LTM and recruited MEF2 to discrete foci within nuclei (Fitzsimons et al 2013). Taken together, these data indicate that when in the nucleus, HDAC4 has the capacity to repress expression of plasticity-related genes, which correlates with memory impairment (Sando et al 2012); however, it also plays a promemory role, as evidenced by the memory impairments that result from reduction of HDAC4 in the adult brain Fitzsimons et al 2013).Here, we sought to increase understanding of the molecular mechanisms through which HDAC4 regulates memory via a two-pronged approach. First, in order to investigate whether the memory deficits we observed following overexpression of HDAC4 were accompanied by alterations in gene expression, we performed RNA sequencing (RNAseq) on heads of flies that overexpressed HDAC4 in the adult brain; however, very few changes were found, suggesting that wildtype (WT) HDAC4 elicits limited transcriptional effects.…”

“…The UAS-HDAC4OE transgenic line harbors a UAS upstream of WT Drosophila HDAC4 fused to an N-terminal FLAG-tag, as previously described (Fitzsimons et al 2013). GMR-HDAC4 was generated by fusing HDAC4 directly under control of GMR by standard methods; human HDAC4 and 3SA were cloned into pUASTattB by standard methods.…”

“…The courtship suppression assay was performed as previously described (Fitzsimons and Scott 2011;Fitzsimons et al 2013).…”

“…To that end, we recently demonstrated that in Drosophila, RNA interference (RNAi)-mediated knockdown of HDAC4 in the adult brain impairs long-term memory (LTM) in the courtship suppression assay, a model of associative memory (Fitzsimons et al 2013). Similarly in humans, loss of one copy of HDAC4 correlates with brachydactyly mental retardation syndrome (BDMR), the neurological symptoms of which include intellectual disability and autism (Williams et al 2010;Morris et al 2012;Villavicencio-Lorini et al 2013), and in mice, conditional knockout of HDAC4 in the brain results in impairments in hippocampal-dependent associative LTM .…”