Protracted Maturation of Cortical Inhibitory Neurons for the Complexity of Higher Cognitive Areas

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

Neurodevelopmental mechanisms in the human brain have emerged to support its larger size, increased complexity, and higher cognitive functions. Despite these benefits, the human brain encounters a variety of risks during development that can lead to developmental disabilities such as autism spectrum disorder (ASD). This evolutionary paradox has prompted a deep investigation into the distinctive developmental mechanisms in the human brain, seeking a new approach to human-based pathologies. One notable process is the protracted maturation of human cortical inhibitory neurons (CIN) during the perinatal period, before and after birth. CINs, a key population for network balance, still migrate postnatally into specific areas important for cognition. Indeed, children with ASD show an abnormal distribution of CINs and alternations in neural oscillations mediated by CIN in several cortical regions. Due to several obstacles, including limited access to the perinatal human brains, we have yet to elucidate how the protracted CIN migration contributes to regional specification and their vulnerability during the perinatal period. This proposal builds on my recent postdoctoral work on comparative analyses. I found immature inhibitory populations along the lateral ventricle (LV) and their regional migrations into the cingulate cortex (CC) and temporal cortex (TC) in the neonatal human brain. Strikingly, these populations are preserved in the large, gyrencephalic human, chimpanzee, and piglet brains, but not small, lissencephalic brains. This work provides a strong justification for utilizing the chimpanzee and piglet brains to study the migration of human CIN in this proposal. Here, I will test the central hypothesis that immature CINs at the perinatal stage have distinct migratory dynamics that differentially contribute to the regional cortical specifications, using the time-laps live imaging on larger brains (Aim 1, K99). Additionally, our gene expression data revealed that late-migratory CIN preferentially expresses ASD-risk genes. I will perturb ASD-risk genes using the CRISPR strategy to test the role of these genes in migration, integration, and differentiation of immature CINs in larger brains (Aim 2, K99). In the independent phase of this proposal, I will further expand my studies based on my significant finding that an additional population of immature inhibitory neurons in the temporal horn of the LV extensively migrate into the middle temporal gyrus (MTG), a part of TC in the neonatal human brain. My approach with comparative histology, single-nucleus RNA transcriptomic, live-imaging, and genetic perturbation techniques will uncover unique properties of CIN development in MTG that drive the structural and functional specification of MTG (Aim 3, R00). This proposal will expand our comprehensive understanding of the contribution of the protracted development of CIN to the specialization of cognitive regions. In turn, exploring the connection between ASD-risk genes and late-maturing CINs may provide greater insight into a novel therapeutic approach for human-based interneuron pathologies during the perinatal period.