Synaptic Analysis of Neuroligin1 function

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DESCRIPTION (provided by candidate): The overarching goal of this proposal is to explore the mature synaptic function of Neuroliginl, a synapse- specific protein implicated in several autism spectrum disorders (ASDs). Molecular biology and mouse genetics will be used together with synaptic physiology to better understand the normal biological function of NL1 and the possible contributions of mutations in this gene to abnormal synaptic function in neuropsychiatric disorders. In addition to providing potential model systems for the study of ASDs, results from this work will contribute significantly to the limited understanding of NL function at mature synapses. In doing so, they may provide new targets for future molecular interventions in psychiatric disorders. Previous work from the hippocampus of NL1 knockout mice demonstrated a 50% reduction in the NMDAR/AMPAR ratio at Schaffer collateral/CA1 synapses. My first two specific aims will specifically address this observation by separately characterizing alterations in AMPAR- and NMDAR-mediated currents in control and NL1 mutant acute hippocampal slice preparations. I will follow these experiments by testing whether NL1 functions in NMDAR-dependent long-term potentiation (LTP) or long-term depression (LTD) at Schaffer collateral-CA1 synapses. Finally, to assess whether NL1 control of synaptic transmission has a pre- or post- synaptic locus, I will use postnatal lentiviral injection in vivo to "rescue" individual cells in NL1 KO mice with point mutants that disrupt either extracellular (3-neurexin binding or intracellular binding to PSD-95. The results of these experiments should both compliment our current in vitro knowledge while enhancing our understanding of the function of NL1 in the mature hippocampal circuit. Autism spectrum disorders (ASDs) comprise a heterogeneous group of neuro-developmental disorders that are highly heritable. Neuroliginl, a molecule found at synapses, has been implicated in familial ASDs. This proposal seeks to better understand the function of NL1 in the mature brain so that disorders resulting from abnormalities in this gene can one day be ameliorated.