Investigating the Role of KIBRA-Dependent Synaptic Function on Hippocampal and Cortical Network Mechanisms Underlying Complex Cognition

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Project Summary Revealing how molecular interactions within single cells contribute to experience-dependent changes in circuit- level neural activity across large-scale brain networks brain is an urgent challenge in neuroscience. Disorders of complex cognition including schizophrenia, bipolar disorder and autism spectrum disorder ultimately manifest via emergent properties of dysfunctional neural networks. While these disorders have strong and overlapping genetic contributions, a clear picture of how heritable factors contribute functionally to pathological symptoms remains elusive. Broadly, my career goal is to delineate how distinct molecular and cellular mechanisms associated with neurodevelopmental psychiatric disease contribute to neuronal circuit dynamics. My graduate work focuses on investigating in vivo network dysfunction following removal of the synaptic scaffolding protein KIBRA, which regulates synaptic plasticity and is genetically associated with natural variation in human memory. KIBRA and the protein complexes it organizes are also associated with several neurodevelopmental disorders. To determine whether KIBRA-dependent plasticity mechanisms regulate behaviorally relevant circuit dynamics, I monitored simultaneous neural activity in both the hippocampus (HC) and frontal cortex (ACC) of mice with forebrain-specific deletion of KIBRA (KIBRA cKO) using in vivo electrophysiology in freely behaving mice. My findings indicate a failure of hippocampal circuits to properly synchronize in response to novel experience in the absence of KIBRA. Based on current results from Aim 1, studies in Aim 2 will evaluate the requirement of KIBRA- dependent plasticity mechanisms for synchronized neural activity that promotes the acquisition of spatial information. This will be done by first examining the integrity and synchrony of HC and ACC network oscillations with respect to behavior to gain insight into network communication between and within these regions. Further experiments will focus on the firing patterns of individual neurons with respect to experience and their coherence to ongoing oscillations in the HC and ACC networks. Firing fields of these neurons predictably change in an experience- and plasticity-dependent manner, which will allow examination of KIBRA-dependent information processing at the single cell level. This will be followed by evaluating the functional role of KIBRA in late postnatal development of the HC and ACC networks by conducting multi-day recordings in juvenile KIBRA KO mice. In Aim 3, I describe my postdoctoral research plan to investigate how mitochondrial metabolism, an understudied and high confidence risk factor for neuropsychiatric disease, influences brain network function. I will gain expertise in in vivo imaging and opto/chemogenetics to complement expertise gained during my PhD work. The integration of my PhD and postdoctoral training will lay the groundwork for a career in neuroscience research that contributes to an understanding of disorders of complex cognition. Findings from these studies will provide insight into how specific psychiatric disease-relevant molecular mechanisms contribute to brain network function and behavior and may highlight new molecular or neurophysiological targets for diagnosis and treatment.