Recent exome sequencing studies have implicated polymorphic BAF complexes (mammalian SWI/SNF chromatin remodeling complexes) in several human intellectual disabilities and cognitive disorders. However, it is currently unknown how mutations in BAF complexes result in impaired cognitive function. Post mitotic neurons express a neuron specific assembly, nBAF, characterized by the neuron-specific subunit BAF53b. Mice harboring selective genetic manipulations of BAF53b have severe defects in longterm memory and long-lasting forms of hippocampal synaptic plasticity. We rescued memory impairments in BAF53b mutant mice by reintroducing BAF53b in the adult hippocampus, indicating a role for BAF53b beyond neuronal development. The defects in BAF53b mutant mice appear to derive from alterations in gene expression that produce abnormal postsynaptic components, such as spine structure and function, and ultimately lead to deficits in synaptic plasticity. Our studies provide new insight into the role of dominant mutations in subunits of BAF complexes in human intellectual and cognitive disorders.
Epigenetic mechanisms regulate processes of neuroplasticity critical to cocaine-induced behaviors. This includes the Class I histone deacetylase (HDAC) HDAC3, known to act as a negative regulator of cocaine-associated memory formation within the nucleus accumbens (NAc). Despite this, it remains unknown how cocaine alters HDAC3-dependent mechanisms. Here, we profiled HDAC3 expression and activity in total NAc mouse tissue following cocaine exposure. Although chronic cocaine did not affect expression of Hdac3 within the NAc, chronic cocaine did affect promoter-specific changes in HDAC3 and H4K8Ac occupancy. These changes in promoter occupancy correlated with cocaine-induced changes in expression of plasticity-related genes. To causally determine whether cocaine-induced plasticity is mediated by HDAC3's deacetylase activity, we overexpressed a deacetylase-dead HDAC3 point mutant (HDAC3-Y298H-v5) within the NAc of adult male mice. We found that disrupting HDAC3's enzymatic activity altered selective changes in gene expression and synaptic plasticity following cocaine exposure, despite having no effects on cocaine-induced behaviors. In further assessing HDAC3's role within the NAc, we observed that chronic cocaine increases Hdac3 expression in Drd1 but not Drd2 -cells of the NAc. Moreover, we discovered that HDAC3 acts selectively within D1R cell-types to regulate cocaine-associated memory formation and cocaine-seeking. Overall, these results suggest that cocaine induces cell-type-specific changes in epigenetic mechanisms to promote plasticity important for driving cocaine-related behaviors. SIGNIFICANCE STATEMENT Drugs of abuse alter molecular mechanisms throughout the reward circuitry that can lead to persistent drug-associated behaviors. Epigenetic regulators are critical drivers of drug-induced changes in gene expression. Here, we demonstrate that the activity of an epigenetic enzyme promotes neuroplasticity within the nucleus accumbens (NAc) critical to cocaine action. In addition, we demonstrate that these changes in epigenetic activity drive cocaine-seeking behaviors in a cell-type-specific manner. These findings are key in understanding and targeting cocaine's impact of neural circuitry and behavior.
Deep space travel presents a number of measurable risks including exposure to a spectrum of radiations of varying qualities, termed galactic cosmic radiation (GCR) that are capable of penetrating the spacecraft, traversing through the body and impacting brain function. Using rodents, studies have reported that exposure to simulated GCR leads to cognitive impairments associated with changes in hippocampus function that can persist as long as one-year post exposure with no sign of recovery. Whether memory can be updated to incorporate new information in mice exposed to GCR is unknown. Further, mechanisms underlying long lasting impairments in cognitive function as a result of GCR exposure have yet to be defined. Here, we examined whether whole body exposure to simulated GCR using 6 ions and doses of 5 or 30 cGy interfered with the ability to update an existing memory or impact hippocampal synaptic plasticity, a cellular mechanism believed to underlie memory processes, by examining long term potentiation (LTP) in acute hippocampal slices from middle aged male mice 3.5-5 months after radiation exposure. Using a modified version of the hippocampus-dependent object location memory task developed by our lab termed "Objects in Updated Locations" (OUL) task we find that GCR exposure impaired hippocampus-dependent memory updating and hippocampal LTP 3.5-5 months after exposure. Further, we find that impairments in LTP are reversed through one-time systemic subcutaneous injection of the histone deacetylase 3 inhibitor RGFP 966 (10 mg/kg), suggesting that long lasting impairments in cognitive function may be mediated at least in part, through epigenetic mechanisms.
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