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

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.