The Class IIa histone deacetylase HDAC4 and neuronal function: Nuclear nuisance and cytoplasmic stalwart?

Histone deacetylase (HDAC) family members are important mediators of epigenetic mechanisms in the regulation of memory formation. Recent studies have revealed that Class IIa HDAC family member HDAC4 contributes essential functions to synaptic plasticity and memory as well as other neurological processes. HDAC4 is localized to both the nucleus and cytoplasm and undergoes subcellular shuttling in response to synaptic activity. In the nucleus, HDAC4 is a repressor of transcriptional programmes, although vertebrate HDAC4 is itself catalytically inactive and repression is facilitated through direct inhibition of transcription factors such as MEF2. In the brain, however, HDAC4 is predominantly cytoplasmic, and a pool of HDAC4 is concentrated in dendritic spines. This review explores and synthesizes the evidence that specific subcellular pools of HDAC4 mediate differential effects on neurological function. Nuclear-restriction of HDAC4 results in down-regulation of plasticity-related genes and memory impairment. However loss of HDAC4 also results in memory deficits through unknown mechanisms. The localization to dendritic shafts and spines, combined with the evidence that cytoplasmic HDAC4 is neuroprotective in some models of neurological dysfunction point to an essential cytoplasmic role. Investigation of extra-nuclear roles of HDAC4, including identification of cytoplasmic binding partners is paramount in order to understand and therefore manipulate its function for potential therapeutic benefit.