Autism-associated ASPM variant causes macrocephaly and social-cognitive deficits in mice

Singh, S.; Kim, H.; Ecevitoglu, A.; Chasse, R.; Ludko, A. M.; Sanganahalli, B.; Gangasandra, V.; Park, S. R.; Yee, S.-P.; Grady, J.; Salamone, J.; Fitch, R. H.; Spellman, T.; Hyder, F.; Bae, B.-I.

doi:10.1101/2025.02.17.638753

bioRxiv · 10.1101/2025.02.17.638753

Autism-associated ASPM variant causes macrocephaly and social-cognitive deficits in mice

Singh, S.·Kim, H.·Ecevitoglu, A.·Chasse, R.·Ludko, A. M.·Sanganahalli, B.·Gangasandra, V.·Park, S. R.·Yee, S.-P.·Grady, J.·Salamone, J.·Fitch, R. H.·Spellman, T.·Hyder, F.·Bae, B.-I.

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Abstract

In autism spectrum disorder (ASD), a neurodevelopmental disorder with social-cognitive deficits, macrocephaly occurs in 20% of patients with severe symptoms. However, the role of macrocephaly in ASD pathogenesis remains unclear. Here, we address the mechanistic link between macrocephaly and ASD by investigating a novel ASD-associated gain-of-function A1877T mutation in ASPM (abnormal spindle-like microcephaly-associated). ASPM is a key regulator of cortical size and cell proliferation expressed in both excitatory and inhibitory neuronal progenitors but not in differentiated neurons. We found that Aspm gain-of-function knock-in mice exhibit macrocephaly, excessive embryonic neurogenesis with expanded outer radial glia, an increased excitatory-inhibitory (E-I) ratio, brain hyperconnectivity, and social-cognitive deficits with male specificity. Our results suggest that macrocephaly in ASD is not a proportional expansion of excitatory and inhibitory neurons, but a shift in the E-I ratio, independent of the expression patterns of the causative gene. Thus, macrocephaly alone can cause a subset of ASD-like symptoms.

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Singh, S., Kim, H., Ecevitoglu, A., Chasse, R., Ludko, A. M., Sanganahalli, B., Gangasandra, V., Park, S. R., Yee, S.-P., Grady, J., Salamone, J., Fitch, R. H., Spellman, T., Hyder, F., Bae, B.-I.. 2025-02-19. Autism-associated ASPM variant causes macrocephaly and social-cognitive deficits in mice. https://doi.org/10.1101/2025.02.17.638753

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