Alternative splicing mechanism in stress.

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PROJECT SUMMARY/ABSTRACT This proposal represents a highly innovative line of research focusing on the role of pre-mRNA splicing in the pathophysiology of chronic stress. Chronic stress is a major risk factor for many neuropsychiatric disorders, including major depressive disorder, anxiety disorder, post-traumatic stress disorder (PTSD), schizophrenia, and addiction. Neurotransmission and synaptic plasticity are known to be dysregulated by chronic stress, leading to long-term neuronal dysfunction and altered emotional and cognitive behaviors. We have novel data showing the dysregulation of splicing factors in the brains of chronically stressed animals. Furthermore, our findings indicate a role for upstream regulatory splicing factors in mediating synaptic function. Dysregulation of pre-mRNA splicing events can lead to neuronal dysfunction due to aberrant protein expression levels and expression of protein isoforms with altered functions. Therefore, we propose to investigate a regulatory pre-mRNA splicing mechanism for the neuronal dysfunction arising from chronic stress. We will do so using animal and cellular models to determine the precise roles of pre- mRNA splicing elements in neuronal function and behavior, and to elucidate how they are dysregulated in chronic stress. We expect results from the proposed studies to provide novel insights into the cellular and molecular mechanisms underlying stress-induced neuropathology and behavior, and to identify potential candidates for future translational therapeutic strategies for stress-related neuropsychiatric disorders and addiction. The studies proposed in this application will provide a strong foundation for furthering our understanding of how pre-RNA splicing events maintain the functional integrity of the CNS as it responds to chronic stress and will inform future stress-related translational studies in major depressive disorder, anxiety disorder, PTSD, schizophrenia, and addiction.