Sousa, A. M. | bioRxiv Science

bioRxiv2023

Multimodal analysis of neuronal maturation in the developing primate prefrontal cortex

The prefrontal cortex (PFC) is critical for myriad high-cognitive functions and is associated with several neuropsychiatric disorders. Here, using Patch-seq and single-nucleus multiomic analyses, we identified genes and regulatory networks governing the maturation of distinct neuronal populations in the PFC of rhesus macaque. We discovered that specific electrophysiological properties exhibited distinct maturational kinetics and identified key genes underlying these properties. We unveiled that RAPGEF4 is important for the maturation of resting membrane potential and inward sodium current in both macaque and human. We demonstrated that knockdown of CHD8, a high-confidence autism risk gene, in human and macaque organotypic slices led to impaired maturation, via downregulation of key genes, including RAPGEF4. Restoring the expression of RAPGEF4 rescued the proper electrophysiological maturation of CHD8-deficient neurons. Our study revealed regulators of neuronal maturation during a critical period of PFC development in primates and implicated such regulators in molecular processes underlying autism.

neuroscience↗

bioRxiv2018

Planar cell polarity pathway and development of the human visual cortex

The radial unit hypothesis provides a framework for global (proliferation) and regional (distribution) expansion of the primate cerebral cortex. Using principal component analysis (PCA), we have identified cortical regions with shared variance in their surface area and cortical thickness, respectively, segmented from magnetic resonance images obtained in 23,800 participants. We then carried out meta-analyses of genome-wide association studies of the first two principal components for each phenotype. For surface area (but not cortical thickness), we have detected strong associations between each of the components and single nucleotide polymorphisms in a number of gene loci. The first (global) component was associated mainly with loci on chromosome 17 (9.5e-32 [≤] p [≤] 2.8e-10), including those detected previously as linked with intracranial volume and/or general cognitive function. The second (regional) component captured shared variation in the surface area of the primary and adjacent secondary visual cortices and showed a robust association with polymorphisms in a locus on chromosome 14 containing Disheveled Associated Activator of Morphogenesis 1 (DAAM1; p=2.4e-34). DAAM1 is a key component in the planar-cell-polarity signaling pathway. In follow-up studies, we have focused on the latter finding and established that: (1) DAAM1 is highly expressed between 12th and 22nd post-conception weeks in the human cerebral cortex; (2) genes co-expressed with DAAM1 in the primary visual cortex are enriched in mitochondria-related pathways; and (3) volume of the lateral geniculate nucleus, which projects to regions of the visual cortex staining for cytochrome oxidase (a mitochondrial enzyme), correlates with the surface area of the visual cortex in major-allele homozygotes but not in carriers of the minor allele. Altogether, we speculate that, in concert with thalamocortical input to cortical subplate, DAAM1 enables migration of neurons to cytochrome-oxidase rich regions of the visual cortex, and, in turn, facilitates regional expansion of this set of cortical regions during development.

neuroscience↗