RNA transcripts encoding the 2C-subtype of serotonin receptor (5HT{2C}) can be modified by up to five adenosine-to-inosine (A-to-l) editing events, a process responsible for the cell-specific expression of as many as twenty-four 5HT{2C} receptor isoforms which may represent a regulatory mechanism by which cells modulate their response to extracellular signals by altering the efficacy and specificity of receptor:G-protein interactions. The 5HT{2C} receptor has been implicated in human psychiatric and behavioral disorders and numerous studies have demonstrated alterations in 5HT{2C} editing in patients diagnosed with anxiety, depression associated with suicide, and in response to antidepressant and antipsychotic treatment. The Emeson lab has developed mutant mouse strains solely expressing either the non- or fully-edited isoform of the 5HT{2C} receptor as a strategy to define the physiologic importance for multiple edited 5HT{2C} isoforms. More recent studies have indicated that repeated, daily stress in adult mice can selectively modulate 5HT{2C} editing patterns in the hippocampus. Exposure to stress is one of the most prominent environmental factors associated with an increased risk of developing mood disorders and efforts to understand the mechanisms underlying these stress-induced alterations and subsequent changes in hippocampal function and neuroplasticity are the focus of Project 4: Stress-Mediated Alterations in Serotonin 2C Receptor Editing and Function.
In Specific Aim I, Emeson proposes to define the onset, persistence, brain region- and substrate-specificity of editing alterations in response to well established models of stress.
In Specific Aim II, Emeson uses molecular tools, pharmacologic agents and mutant mouse models to reverse the observed changes in editing as a strategy to define the signaling pathways and molecular mechanisms underlying 5HT{2C} expression.
In Specific Aim III, Emeson develops a novel BAG transgenic reporter mouse to assist in defining the functional changes associated with altered 5HT{2C} receptor editing and to examine other indices of hippocampus-specific alterations in 5HT{2C} signaling with the goal of understanding the role(s) that this RNA processing event plays in adaptive responses to stress and the pathogenesis of mood disorders.

Public Health Relevance

Chronic stress paradigms in animals recapitulate many of the core behavioral characteristics of mood disorders and such stress can exert marked effects on cognitive function and hippocampal synaptic plasticity. The proposed studies will examine the roles and mechanisms by which stress, both during early life and in adulthood, programs adaptive responses through altered RNA editing of transcripts encoding the 2C-subtype of serotonin receptor.

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National Institute of Mental Health (NIMH)
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Vanderbilt University Medical Center
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