Circuitry mechanisms underlying normal and aberrant adult hippocampal neurogenesis

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Adult neurogenesis recapitulates the whole process of neuronal development in a mature central nervous system, from proliferation and fate specification of adult neural progenitors, morphogenesis, migration, axon/dendritic development, and finally synapse formation, culminating in the full integration of new neurons into the existing circuitry. Cumulative evidence suggests that new neurons participate in specific brain functions and aberrant adult neurogenesis may contribute to brain disorders. During the past 11 years, my laboratory has been using adult hippocampal neurogenesis as an experimental model system to elucidate molecular mechanisms regulating the neuronal development. Furthermore, we have been using this system to explore novel functions of risk genes for mental disorders in neuronal development. A number of susceptibility genes for schizophrenia have been identified from human genetic studies. Among them, DISC1 (disrupted-in- schizophrenia 1) was initially identified at the breakpoint of a balanced (1;11)(q42;q14) translocation that co- segregates with schizophrenia in a large Scottish family. Recent studies have further implicated DISC1 as a general risk factor not only for schizophrenia, but also for bipolar disorders and major depression. Functionally, DISC1 is a multifunctional scaffold protein that regulates neuronal development during embryonic, early postnatal and adult neurogenesis. The current project is built upon discoveries made in my laboratory during the past 11 years, both at the cellular lever on sequential phases of new neuron development during adult neurogenesis and critical roles of DISC1 in regulating multiple phases of newborn granule cell development in the adult hippocampus and at the system level for the requirement of DISC1 function specifically in newborn neurons on hippocampal-dependent cognitive and affective behavioral deficits. How genetic dysregulation of DISC1 contributes to aberrant adult neurogenesis and a wide spectrum of mental disorders at the circuitry level is unknown. Our overall goal of this project is to elucidate local internneuron circuitry mechanisms underlying normal neuronal development during adult hippocampal neurogenesis and aberrant development due to DISC1-deficency. Our overall hypothesis is that genetic risk factors for mental disorders interact with specific neurona circuit activity to manifest developmental defects. We are uniquely positioned to address this fundamental questions using genetic, optogenetic, trans-synaptic tracing and imaging tools we have developed. Our proposed studies may not only provide novel mechanistic insights of normal and aberrant neuronal development, but also lead to better understanding of certain mental disorders. One example is our hypothesis-driven identification of epistatic interaction between DISC1 and FEZ1 and between DISC1 and NKCC1 in affecting schizophrenia risks and brain function in humans, all based on our studies from animals using adult neurogenesis as a model system.