Abstract
AbstractThe dorsolateral prefrontal cortex (dlPFC) is an evolutionarily derived cortical region in primates critical for high-level cognitive functions and implicated in various neuropsychiatric disorders1–8. The cells that compose the dlPFC, especially excitatory and inhibitory neurons, undergo extensive maturation throughout midfetal and late-fetal development, during which critical neurodevelopmental events, such as circuit assembly and electrophysiological maturation of neurons, occur3,8–15. Despite the relevance of neuronal maturation in several neurodevelopmental and psychiatric disorders8,16, the molecular mechanisms underlying this process remain largely unknown. Here, we performed an integrated Patch-seq and single-nucleus multiomic analysis of the rhesus macaque dlPFC to identify genes governing neuronal maturation from midfetal to late-fetal development. Our multimodal analysis identified gene pathways and regulatory networks important for the maturation of distinct neuronal populations, including upper-layer intratelencephalic-projecting neurons. We identified genes underlying the maturation of specific electrophysiological properties of these neurons. Furthermore, gene knockdown in organotypic slices revealed thatRAPGEF4regulates the maturation of resting membrane potential and inward sodium current. Using this strategy, we also found that the knockdown ofCHD8, a high-confidence autism spectrum disorder risk gene, in human slices led to deficits in neuronal maturation, via the downstream downregulation of several key genes, includingRAPGEF4. Our study revealed novel regulators of neuronal maturation during a critical period of prefrontal development in primates and implicated such regulators in molecular processes underlying autism.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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