Neural function of the human memory-associated protein KIBRA: bridging molecular to circuit-level function

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Understanding the biological basis of complex behavior is a major challenge in neuroscience, and disorders of complex brain function exact an enormous social and financial burden. Solving this problem requires understanding how information processing integrates across molecular, cellular, and circuit levels to influence behavior, and how disease-associated risk factors impact such information processing. Numerous studies demonstrate that common variants of KIBRA (enriched in KIdney and BRAin) associate with human memory performance. KIBRA polymorphisms and gene expression also associate with disorders of complex brain function including schizophrenia (SCZ) and autism spectrum disorder (ASD), and a strikingly large proportion of neuronal KIBRA binding partners associate with SCZ, bipolar disorder, and/or ASD. Thus, KIBRA represents an ideal candidate to reveal molecular mechanisms that control synaptic plasticity and circuit function responsible for normal cognitive processes that are impaired in mental illness. We recently identified KIBRA (enriched in KIdney and BRAin) as a regulator of AMPAR trafficking, synaptic plasticity, and learning and memory in rodents, but the mechanisms by which KIBRA influences these processes and the impact on circuit dynamics remain unclear. This project aims to elucidate KIBRA function across multiple levels of information processing via three aims: 1) identify molecular mechanisms by which KIBRA protein complexes respond to neuronal activity and regulate AMPAR trafficking, 2) determine the molecular and developmental requirements for KIBRA in bidirectional synaptic plasticity, and 3) establish the role of KIBRA in regulating circuit dynamics. Intriguingly, despite robust expression of KIBRA in both the juvenile and adult brain, deficits in synaptic plasticity do not emerge until young adulthood in constitutive KIBRA knockout (KO) mice, a time course consistent with the onset of neurodevelopmental disorders such as SCZ and BPD. Thus, our experiments will also evaluate developmental maturity as a factor impacting the function of KIBRA protein complexes and the neural response to perturbation of KIBRA. To accomplish these goals, we will use domain mutants to identify KIBRA interactors required for trafficking of endogenous AMPARs, employ biochemical and advanced imaging methods (Fluorescence Fluctuation Spectroscopy) to identify activity-regulated dynamics and stoichiometry of KIBRA complexes, examine functional and structural synaptic plasticity in acute brain slices from constitutive and conditional KIBRA KO mice, and perform in vivo electrophysiology in freely behaving mice to evaluate the role of KIBRA in behaviorally-driven circuit dynamics. These proposed studies will reveal critical insight into the function of human-memory- and neurodevelopmental disorder-associated KIBRA complexes at multiple levels of information processing, with broad implications for understanding the mechanisms and neurodevelopmental vulnerabilities underlying complex behavior.