Consequences of HDAC2 Inhibition in VTA-NAc circuitry

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From parent grant ABSTRACT Bipolar disorder is a common psychiatric disease with few treatment options and no cure. One of the most commonly prescribed medications for treatment of acute mania and mood stabilization is the anticonvulsant drug, valproate (VPA; trade name Depakote). This medication has been used since the mid-1990s, however not everyone responds equally to VPA in terms of therapeutic efficacy and it can produce multiple, often severe side effects. Moreover, VPA has a variety of molecular targets and it is unclear which targets are therapeutically relevant. Better understanding of the molecular mechanisms that normalize mania in response to VPA could lead to more targeted treatments in the future which produce a higher therapeutic response with less side effects. In the first funding cycle of this grant, we discovered that the therapeutic actions of VPA appear to occur via it’s inhibition of a protein called histone deacetylase 2 (HDAC2) specifically in a part of the brain that contains a large number of dopaminergic neurons, the ventral tegmental area (VTA). HDAC2 is involved in the regulation of gene expression on a wide scale, so while the inhibition of this protein is perhaps more targeted than VPA treatment, it is still advantageous for us to identify the important genes who’s expression is changed as a result of HDAC2 inhibition in the VTA. To identify these targets, we will first determine which genes are normally bound by HDAC2 and what changes to histone acetylation occur in response to HDAC2 inhibition in the VTA using two animal models that have a behavioral profile that is strikingly similar to human mania and increased dopaminergic activity in the VTA. We will then determine which gene and protein expression changes occur with HDAC2 inhibition and combine these results with those of the first Aim, and our prior results, to determine the particular proteins that might be likely therapeutic candidates. In Aim 3 we will then determine the impact of HDAC2 inhibition and direct target genes of HDAC2 on VTA dopaminergic activity and signaling in our mouse models to help identify the mechanisms by which HDAC2 target genes might normalize human mania. Taken together, this study will help us to identify novel therapeutic targets and their mechanism of action for the treatment of bipolar disorder.