Kylie S. Chew - US grants

? DESCRIPTION (provided by applicant): The adult nervous system must accomplish a vast variety of functions including processing environmental stimuli such as light, sounds, and odors, generating motion and learning, and regulating homeostasis. During development, neurons must wire into precise neural networks in order to drive these complex behaviors. Initially, neurons make grossly accurate connections and establish a coarse level of organization, and then these connections are refined in both number and strength based on neural activity. Activity-dependent mechanisms are essential for the developing brain to mature and have recently been implicated as a molecular basis for the pathophysiology of several neuropsychiatric disorders, including schizophrenia and autism spectrum disorders. The major goal of this proposal is to identify components of the molecular program by which activity refines developing neural circuits. Research in the Shatz lab discovered a surprising role for major histocompatibility complex class I (MHCI) proteins in activity-dependent refinement of neural networks. Observation of MHCI expression in neurons was unexpected because the brain had historically been considered an immunoprivileged environment and the well-established function of MHCI molecules is in the immune system where they are involved in the recognition of self versus foreign. The presence of MHCIs in neurons is additionally notable because in genome-wide association studies, polymorphisms in the MHC genomic cluster are associated with several neuropsychiatric disorders, and in fact the MHC locus has the strongest association with schizophrenia. The Shatz lab further revealed that two classical MHCI genes (H-2Db and H-2Kb) are regulated by activity and required for the synaptic pruning that refines initial connections in the developing visual system. However, there are more than 50 MHCI genes, and yet to date, only these two have been studied in brain. I present here preliminary data that a non-classical MHCI, Qa-1, which has yet to be examined in the nervous system, is expressed by neurons in visual cortex. In the immune system, Qa-1 interacts with different receptors (CD94/NKG2s) than H-2Db and H-2Kb. I additionally present preliminary data that components of Qa- 1's cognate receptors, CD94/NKG2s, are also expressed by neurons. The central goal of this proposal is to use genetic, histological, electrophysiological, and biochemical techniques to elucidate functions of Qa-1 and its receptors in synaptic pruning and plasticity during development using the visual system as a model. I will specifically test the hypothesis that Qa-1 is a component of the pathway that executes activity-dependent changes in neural networks and that by interacting with different receptors than classical MHCIs, Qa-1 serves a distinct function in this developmental process. The long-term aim of this research is to contribute to our understanding of the molecular underpinnings for the pathophysiology of neurodevelopmental disorders.