Role of neuronal migration genes in synaptogenesis and plasticity

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DESCRIPTION (provided by applicant): Spine and synapse density are abnormal in clinical material and in animal models of autism and schizophrenia, including in mice bearing mutations in the fragile-X mental retardation protein (FMRP) and the Rett gene, MeCP2. A major focus in mental health research is defining the mechanisms regulating formation and persistence of synapses in developing brain. Current hypotheses regarding autistic behaviors include not only formation of faulty synaptic contacts but also failure to successfully prune synapses once formed or make new connections during childhood development. Filopodia are the most likely predecessor of dendritic spines, the sites of most synapses, and both rely on their motility in order to sample, test and finally make contacts and synapses to form proper circuits. While a lot of dendritic spines are maintained throughout life, many spines are eliminated and new spines are formed that could reflect memories lost or new contacts, and thus memories, gained. While there are strong indications of its potential importance, the role of Lis1 in signal transduction and post-migration neuronal motility is an essentially uncharted area of investigation. Our laboratory has previously shown that Lis1 significantly influences the regulation of small GTPases RhoA, Rac1 and Cdc42, that Lis1 happloinsufficiency impairs the activation of these Rho-family GTPases upon NMDA-receptor mediated calcium influx, and that is consistent with a signal transduction role for Lis1. Moreover, Lis1 happloinsufficiency is associated with marked reduction in filopodia formation on neurites of hippocampal and cerebellar neurons. We propose to demonstrate that Lis1 plays a prominent role in dendritic filopodia and spine formation and motility that translates into synapse formation and stability. This will further elucidate a new role of Lis1, as a molecule important for synaptogenesis and plasticity. We will investigate the dependence of Lis1 levels on the motility of dendritic filopodia and spines. Using spining-disc confocal and two-photon imaging, we will analyze development and morphology of both filopodia and spines in in vitro and in vivo systems, respectively. Finally, we will conduct experiments that will focus on understanding molecular mechanisms governing these events by analyzing known Lis1 interactors, including the nudE isoform NudE-like 1 (NDEL1) and NDEL1 interacting protein DISC1. Lis1 may provide a critical link between external cues and cytoskeletal modulation underpinning activity-dependent synaptic plasticity. PUBLIC HEALTH RELEVANCE: This project combines genetics, cellular and systems neurobiology with the goal of understanding how the brain is affected in mental health disorders. One of the mechanisms underlying mental health diseases, specifically of schizophrenia and autism, is improper connection between neurons that in turn results in overall abnormal neural circuit function. We will investigate the role of Lis1 in the regulation of proper formation and elimination of connections between neurons that must be carefully orchestrated throughout development.