Pattabiraman, K. | bioRxiv Science

bioRxiv2019

Regulation of Prefrontal Patterning, Connectivity and Synaptogenesis by Retinoic Acid

The prefrontal cortex (PFC) and its reciprocal connections with the mediodorsal thalamus (MD) are crucial for cognitive flexibility and working memory1-4 and are thought to be altered in several disorders such as autism spectrum disorder5, 6 and schizophrenia6-9. While developmental mechanisms governing regional patterning of the rodent cerebral cortex have been characterized10-15, the mechanisms underlying the development of PFC-MD connectivity and the lateral expansion of PFC with distinct granular layer 4 in anthropoid primates16-23 have not been elucidated. Here we report increased concentration of retinoic acid (RA), a signaling molecule involved in brain development and function24, 25 in the prospective PFC areas of human and macaque, compared to mouse, during mid-fetal development, a crucial period for cortical circuit assembly. In addition, we observed the lateral expansion of RA synthesizing enzyme, ALDH1A3, expression in mid-fetal macaque and human frontal cortex, compared to mouse. Furthermore, we found that enrichment of RA signaling is restricted to the prospective PFC by CYP26B1, a gene encoding an RA-catabolizing enzyme upregulated in the mid-fetal motor cortex. Gene deletion in mice revealed that RA signaling through anteriorly upregulated RA receptors, Rxrg and Rarb, and Cyp26b1-dependent catabolism is required for the proper molecular patterning of PFC and motor areas, the expression of the layer 4 marker RORB, intra-PFC synaptogenesis, and the development of reciprocal PFC-MD connectivity. Together, these findings reveal a critical role for RA signaling in PFC development and, potentially, its evolutionary expansion.

neuroscience↗

bioRxiv2019

Hominini-Specific Regulation of CBLN2 Increases Prefrontal Synaptogenesis

The similarities and differences between nervous systems of various species result from developmental constraints and specific adaptations 1-4. Comparative analyses of the prefrontal cortex (PFC), a region of the cerebral cortex involved in higher-order cognition and complex social behaviors, have identified confirmed and putative human-specific structural and molecular changes 4-8. For example, one crucial specialization involves the anterior-posterior gradient in synaptic density, with a disproportionately higher number of dendritic spines specifically in the human PFC compared to other analyzed primates 5. These changes are likely mediated by divergence in spatio-temporal patterns of gene expression 9-17, which are prominent in the mid-fetal human cerebral neocortex 15,18-20. Analyzing developmental human and macaque brain transcriptomic data 15,20, we identified a transient PFC- and laminar-specific upregulation of the gene encoding cerebellin 2 (CBLN2), a neurexin (NRXN) and glutamate receptor delta (GRID/GluD)-associated synaptic organizer 21-27, in human mid-fetal development coinciding with the initiation of synaptogenesis. Moreover, we show that this difference in expression level and laminar distribution of CBLN2, is due to Hominini-specific deletions affecting SOX5 binding sites within a retinoic acid-responsive CBLN2 enhancer. In situ genetic humanization of the mouse Cbln2 enhancer drives increased and ectopic laminar Cbln2 expression and promotes glutamatergic and GABAergic synaptogenesis specifically in the PFC. These findings identify a putative genetic and molecular basis for the disproportionately increased connectivity in the Hominini PFC and suggest a developmental mechanism linking dysfunction of the NRXN-GRID-CBLN2 complex, to the pathogenesis of neuropsychiatric disorders.

neuroscience↗