Depression is considered one of the most serious disorders in today's society, with a lifetime prevalence as high as 16.2% in the US adult population. The introduction of the first pharmacological antidepressant medications in the 1950s, and subsequent development of drugs with lower side-effect profiles has greatly improved the therapeutic outlook for depressed patients. Notably, all the antidepressant drugs now in use modulate monoamine neurotransmission and take six to eight weeks to exert their effects. Still, treatment-resistant depression, which typically refers to inadequate response to at least one antidepressant trial of adequate dose and duration, affects up to 50-60% of patients. Therefore, it will be necessary to test and develop antidepressants with conceptually novel mechanisms of actions and a more rapid therapeutic response. The focus of this application is on pre-clinical studies to assess the antidepressant potential of a novel class of therapeutic drugs, historic deacetylase inhibitors (HDACi). Our central goals are to 1) find out if HDACi's that cross the blood-brain barrier alter test performance in rodent models for anxiety, behavioral despair and learned helplessness and 2) to study HDACi-induced chromatin-remodeling, including histone acetylation, at proximal promoter sequences of genes that are involved in neurotrophin and/or angiogenic-endothelial signaling pathways. The behavioral experiments (Aim #1) are guided by preliminary data demonstrating that mice treated for 14-16 days with the HDACi, sodium butyrate, show lower levels of behavioral despair, in comparison to controls. The chromatin studies (Aim #2) will rely on immunoprecipitation of hippocampal extracts with site- and modification-specific anti-histone antibodies, in conjunction with quantitative real time PCR for proximal promoter sequences and RT-PCR for coding sequences of 10 neurotrophic and angiogenic factors that are thought to play a role in the neurobiology or treatment of depression. It is expected that these novel approaches will provide promising first insights into the antidepressant potential of HDACi's and will establish the epigenetic modification of hippocampal chromatin as an important molecular mechanism for the neurobiology of depression.
|Jiang, Yan; Langley, Brett; Lubin, Farah D et al. (2008) Epigenetics in the nervous system. J Neurosci 28:11753-9|
|Schroeder, Frederick A; Lin, Cong Lily; Crusio, Wim E et al. (2007) Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol Psychiatry 62:55-64|