Neural circuitry mechanisms regulating adult hippocampal neurogenesis

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Project Summary Adult hippocampal neurogenesis recapitulates the entire process of neurodevelopment in a specialized neurogenic niche within the mature dentate gyrus (DG). The proper maturation and integration of these adult- born neurons are crucial for cognitive functions and mood regulation. Thus, dysregulation of adult-born neurons by developmentally-expressed genes, such as DISC1 (Disrupted-in-schizophrenia 1), leads to cognitive and affective behavioral deficits. The DG neurogenic niche consists of multiple cell populations including a diverse group of local interneurons with distinctive electrophysiological, molecular, and innervation properties. However, the specific neural circuits that regulate various developmental processes of the newborn neurons are unknown, yet such knowledge is needed to guide rational therapeutic strategies to treat disorders arising from dysregulated adult hippocampal neurogenesis. Using optogenetic and electrophysiological approaches, we recently identified two genetically distinct local interneuron inputs onto immature neurons: perisomatic-targeting parvalbumin (PV) and axo-dendritic targeting somatostatin (SOM) expressing interneurons. How distinct local interneurons and their circuitry connections encode and regulate various developmental processes of newborn neurons during adult hippocampal neurogenesis is unknown. We hypothesize that genetically distinct interneuron circuits regulate discrete developmental processes of newborn neurons. Interestingly, we found that newborn neurons with DISC1 deficiency receive aberrant local interneuron inputs from PV and SOM neurons. Furthermore, we found that dendritic and spine development of newborn neurons with DISC1 deficiency were differentially regulated by local PV and SOM interneuron activities. Together, these data suggested that genetic dysregulation of DISC1 may drive aberrant development of newborn neurons in an interneuron circuit-specific fashion. We therefore hypothesize that manipulating activities of distinct local interneurons and their circuitry connections will exacerbate or normalize specific aspects of aberrant development in newborn neurons with DISC1 deficiency. Our results will reveal the role of distinct neural circuits for encoding specific aspects of normal and aberrant neurodevelopment, and guide treatment strategies targeting adult hippocampal neurogenesis.