TEMPORAL AND CELLULAR EXPRESSION OF ASD-ASSOCIATED GENES IN THE NEOCORTEX​

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental condition currently affecting 1 in 100 children worldwide. Epidemiological studies have identified several highly penetrant genetic risk factors for ASD and neuroimaging analysis frequently indicate increased brain volume and abnormal neuronal connectivity in ASD patients. Despite the strong genetic basis, ASD presents with striking clinical heterogeneity, posing a major challenge in identifying common neurobiological mechanisms. ASD has long been studied as a disorder of synaptic dysfunction, but increasing evidence suggests embryonic neurogenesis as the point where the genetic conditions start to manifest at the cellular level. In this study, we use single-cell RNA sequencing to characterize the temporal and cellular expression profiles of ASD-associated genes in the neocortex and show that several ASD-associated genes are enriched in neurons while other are enriched or only present in neocortical progenitors. Additionally, we analyzed the expression of ASD-associated genes in the neocortex of Brn1/2 knockout mice. We have recently shown that the transcription factors BRN1/2 are essential regulators of progenitor behavior, controlling both their proliferative capacity and the switch from direct to indirect neurogenesis required for proper brain size. Interestingly, our preliminary results show that the expression of several ASD-associated genes is altered in the progenitor cells of Brn1/2 knockout mice suggesting that at least certain ASD-associated genes might play an important role during the earliest stages of neurodevelopment.