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.

Public Health Relevance

Research Narrative Schizophrenia etiology is thought to involve the interaction between genetic and diverse environmental insults during brain development. Despite significant progress in understanding both genetic susceptibility and neuronal circuit dysfunction in schizophrenia, fundamental gaps exist in our knowledge about how neural circuitry mechanisms may interact with genetic susceptibility to affect neuronal development. Furthermore, cumulative evidence suggests that schizophrenia is marked by abnormal hippocampal structure and disrupted adult hippocampal neurogenesis. How genetic risks contribute to aberrant adult hippocampal neurogenesis at the circuitry level is unknown. Our proposed studies will provide novel cellular and circuitry mechanisms underlying aberrant neurodevelopment associated with genetic risks, and lead to better understanding of the etiology for certain mental disorders such as schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
3R01MH111773-03S1
Application #
9667500
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Panchision, David M
Project Start
2016-09-26
Project End
2020-07-31
Budget Start
2018-08-10
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Liu, Kai; Kim, Juhyun; Kim, Dong Won et al. (2017) Lhx6-positive GABA-releasing neurons of the zona incerta promote sleep. Nature 548:582-587
Bao, Hechen; Asrican, Brent; Li, Weidong et al. (2017) Long-Range GABAergic Inputs Regulate Neural Stem Cell Quiescence and Control Adult Hippocampal Neurogenesis. Cell Stem Cell 21:604-617.e5
Liu, Kai; Kim, Juhyun; Kim, Dong Won et al. (2017) Corrigendum: Lhx6-positive GABA-releasing neurons of the zona incerta promote sleep. Nature 550:548