Functional genomic studies have identified a convergence of autism risk factors during mid-fetal cerebral cortical development^1-2, a crucial period for the assembly for cortical circuits. During mid-fetal development, the largest structure in the human cerebral cortex is the subplate layer, which is located directly below the cortical plate. The subplate layer consists of heterogenous populations of early-born neurons, which are greatly expanded in primates compared to rodents, specifically in association areas of the cortex. Disruption of the subplate layer, which has been described in people with ASD, leads to the disruption of various cortical circuits, including regional thalamocortical circuits and altered balance of cortical excitation and inhibition³.

Despite its essential role in cortical development and association with ASD, there has been minimal molecular characterization of the mouse or primate subplate. For example, there is no delineation of the number of neuronal populations in the subplate layer, their associated circuits or comparative analysis of conserved and species-specific populations.

To address this issue, Kartik Pattabiraman has created a mouse-based strategy to selectively label and manipulate subplate neurons across developmental and postnatal stages (unpublished). The Pattabiraman lab plans to combine this technique with single cell-level transcriptomic and viral circuit tracing approaches to spatiotemporally characterize subplate neurons and their long-range connections. Prioritized population-specific genes including differentially expressed ASD alleles and genes involved in circuit assembly will be characterized using comparative profiling of expression and conditional deletion in both cortical and subplate neurons.

Findings from this study are expected to link ASD risk alleles to specific populations and circuits of the subplate layer, as well as characterize an essential developmental organizer associated with ASD.

1. Shibata M.. et al. Nature 598, 433–408 (2021) PubMed
2. Willsey A.J. et al. Cell 155, 977–1007 (2013) PubMed
3. Molnár Z. et al. Science 370, eabb2153 (2020) PubMed