Effects of maternal immune activation on offspring GABA circuitry and behavior

New York State Psychiatric Institute Dba Research Foundation For Mental Hygiene, Inc, New York NY

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Abstract

? DESCRIPTION (provided by applicant): My career goal is to conduct independent translational research using animal systems to understand neurobiological mechanisms that underlie behavioral abnormalities relevant to psychopathology, with the overall goal of developing new therapeutic strategies. My research interests center on understanding: 1) How prenatal maternal immune activation (MIA), an early environmental risk factor for multiple forms of psychopathology, alters the function of discrete GABAergic interneuron sub-populations in the prefrontal cortex (PFC), ventral hippocampus (vHipp) and basolateral amygdala (BLA) and 2) How activity in these same interneuron populations modulates cognitive and affective behaviors. By refining our understanding of the contribution of different categories of interneurons to prefrontal, hippocampal and amygdalar function at both an electrophysiological and behavioral level I hope to generate more precise ideas of how to correct GABAergic imbalances in patients with cognitive and affective symptoms. This K01 career development award would provide the protected time to gain the technical and intellectual training I require to address the above questions, facilitating my transition towards establishing an independent research program. My primary expertise is in translational mouse models, and the molecular, cellular, physiological and behavioral assays used to characterize them. My career development plan expands on this background, and proposes essential training in optogenetic techniques, intellectual training in the field of cognitive and affective behaviors, and further instruction in professional development skills such as grant writing and laboratory management. Research Project. Abnormalities in PFC GABAergic interneurons are hypothesized to be integral to the pathophysiology of several psychiatric disorders. However, the specific populations of GABAergic interneurons that are functionally affected, and their relationship to behavioral abnormalities, are not well- understood. Animal models of environmental or genetic risk factors for psychiatric disease provide an opportunity to directly assay functional changes in specific populations of PFC GABAergic interneurons that are relevant to mental disorders. My preliminary studies in a murine model of maternal immune activation uncovered a profound reduction in PFC GABAergic transmission in adult MIA offspring. In this proposal I will use optogenetics with slice electrophysiology to uncover which populations of PFC interneurons contribute to this deficit. Next, I will explore the consequences of these alterations for cognitiv and affective behaviors using in vivo optogenetics. Finally, I will investigate whether GABAergic deficits in adult MIA offspring are specific to the PFC by examining GABAergic transmission in the vHipp and BLA, as well as the role of different populations of vHipp and BLA interneurons in cognitive and affective behaviors.