The Regulation of Stress-Induced Synaptic Responses by Histone Deacetylases in the Prefrontal Cortex (Completed Spring, 2015)

The prefrontal cortex (PFC), a region responsible for higher-order cognitive functions, such as decision-making, attention and working memory, is highly influenced by stress and corticosteroid stress hormones. Recently, work in our lab has shown that acute exposures to stress enhances cognitive function in the PFC by potentiating glutamatergic transmission via a mechanism dependent on the glucocorticoid receptor (GR) and its downstream target SGK (serum & glucocorticoid-inducible kinase). In contrast, we have found that chronic exposures to stress impair cognitive function by reducing glutamatergic transmission via a mechanism also dependent on GR.

The goal of this dissertation is to identify key molecular regulators of the stress response in the PFC. To do so, we examined the role of histone deacetylases (HDACs), a family of enzymes that are most well-known for regulating epigenetic changes in gene expression but are also critical for other cellular functions such as steroid hormone signaling. With respect to acute stress, we chose to focus on HDAC6, a unique member of the HDAC family that targets non-histone cytoplasmic proteins and regulates GR activation via acetylation of chaperone protein Hsp90. We found that HDAC6 inhibition or knockdown blocked the enhancement of glutamatergic transmission and glutamate receptor trafficking by acute stress in vivo or corticosterone treatment in vitro. In addition, HDAC6 inhibition blocked the up-regulation of SGK in animals exposed to acute stress. Furthermore, HSP90 inhibition or knockdown produced a similar blockade of the acute stress-induced enhancement of glutamatergic signaling. Taken together, these findings have identified HDAC6 as a key molecule gating the effects of acute stress on synaptic functions in the PFC.

With regards to repeated or chronic stress, we chose to investigate HDAC2, an HDAC which plays an important role in synaptic plasticity and learning and memory via epigenetic gene modification. Recent evidence has shown HDAC2 modulates responses to chronic stress in the nucleus accumbens (NAc), an important reward pathway. We thus surmised that HDAC2 may have a similar function in the PFC.  In our study, we found that inhibition of HDAC2 blocked the decrease in PFC glutamatergic transmission by chronic stress in vivo. This suggests that HDAC2 may be a key regulator of chronic stress-induced synaptic changes in the PFC and that HDAC2 inhibition may be protective against cognitive impairments caused by long-term stress exposure. Treatment with various HDAC inhibitors has emerged as a promising new strategy for therapeutic intervention neuropsychiatric diseases. Our findings contribute to this trend and point to a novel use for HDAC inhibitors in the realm of stress and stress-related conditions. 

Zhen Yan, PhD