Mechanisms by Which Macrocephaly Underlies Autism Spectrum Disorder

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PROJECT SUMMARY/ABSTRACT Autism spectrum disorder (ASD) is a highly heritable, heterogeneous neurodevelopmental disorder affecting 1 in 53 children in the US. The prefrontal cortex, which mediates social cognition and language, is oddly enlarged in at least 15% of patients with ASD who suffer from severe symptoms. Macrocephaly (large brain) is caused by excessive proliferation of cortical progenitors, and progenitors derived from ASD patients show excessive proliferation. However, the extent to which prefrontal macrocephaly itself contributes to the pathophysiology of ASD is unclear. ASPM (abnormal spindle-like microcephaly-associated) is a neurodevelopmental gene that determines cortical size, and may play a role in macrocephaly, as well as in ASD. ASPM controls cell proliferation, and its loss-of-function mutations are the most common cause of genetic microcephaly (small brain) that are particularly severe in the prefrontal cortex. Importantly, it is expressed in cortical progenitors but not in neurons. Recently, de novo variants in ASPM have been associated with ASD. Our preliminary data show that one such variant increases ASPM protein levels in cultured cells, suggesting gain-of-function mutation. Furthermore, we generated Aspm knock-in mice with the gain-of-function mutation, which show excessive neurogenesis, perinatal macrocephaly, and abnormal social behavior recapitulating ASD-like symptoms. Our long-term goal is to understand the mechanisms by which abnormal cerebral cortical development underlies functional abnormalities in ASD. Our central hypothesis is that excessive embryonic neurogenesis, which results in macrocephaly, is sufficient to elicit some ASD-like behaviors by disturbing cell signaling and composition in the postnatal brain. To test the hypothesis, we will leverage the ASD-associated gain-of-function mutation in ASPM, and examine Aspm knock-in mice in three Specific Aims. Thus, we will (Aim 1) investigate the neurodevelopmental trajectory using immunostaining, (Aim 2) determine changes in cell composition and signaling using single-nucleus RNA sequencing, (Aim 3) social cognitive behaviors in Aspm knock-in mice. Our proposed research is significant as we directly address the pathophysiological role of macrocephaly in ASD. It is innovative as we analyze a novel ASD mouse model with a gain-of-function mutation in the neurodevelopmental gene ASPM using diverse, state-of-the-art techniques. Macrocephaly is observed in some ASD patients with severe symptoms. However, the extent to which macrocephaly itself contributes to ASD is unclear. Our novel Aspm knock-in mice carry an ASD-associated mutation and display perinatal macrocephaly with abnormal social behavior. Exploring dysregulated cell types and signaling pathways in Aspm knock-in mice may provide novel therapeutic interventions for ASD.