Multimodal analyses reveal genes driving electrophysiological maturation of neurons in the primate prefrontal cortex

Abstract

The dorsolateral prefrontal cortex (dlPFC) is a derived cortical area in primates that is involved in myriad high-cognitive functions and is associated with several neuropsychiatric disorders. Here, we performed Patch-seq and single-nucleus multiomic analyses of the rhesus macaque dlPFC to identify genes governing neuronal maturation during midfetal to late-fetal development. Our multimodal analyses have identified genes and pathways important for the maturation of distinct neuronal populations as well as genes underlying the maturation of specific electrophysiological properties. Using gene knockdown in macaque and human organotypic slices, we functionally tested the role of RAPGEF4, a gene involved in synaptic remodeling, and CHD8, a high-confidence autism spectrum disorder risk gene, on the electrophysiological and morphological maturation of excitatory neurons in the macaque and human fetal dlPFC.

Rigor and reproducibility in human brain organoid research: Where we are and where we need to go

“…Finally, patch-seq, a novel advancement, merges patch clamp with single-cell sequencing ( Cadwell et al., 2016 ), broadening our understanding of the molecular underpinnings of neuronal function. Patch-seq has elucidated gene expression signatures underlying neuronal activity across various brain slice models, from mouse ( Foldy et al., 2016 ) to non-human primate ( Gao et al., 2023 ) and human ( Berg et al., 2021 ), as well as in hPSC-derived neurons ( van den Hurk et al, 2018 ). By correlating electrical activity with transcriptome profiles at the level of individual neurons, patch-seq offers a comprehensive view of neuronal diversity and function in organoids.…”