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

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social-cognitive deficits.
• Macrocephaly (enlarged head circumference) is observed in approximately 20% of individuals with severe ASD.
• The precise role of macrocephaly in ASD pathogenesis is not well understood.

Purpose of the Study:

• To investigate the mechanistic link between macrocephaly and ASD.
• To examine the impact of a novel ASD-associated gain-of-function mutation in the *ASPM* gene (abnormal spindle-like microcephaly-associated).

Main Methods:

• Utilized *Aspm* gain-of-function knock-in mouse models.
• Analyzed neurogenesis, radial glia expansion, and excitatory-inhibitory (E-I) neuronal ratios.
• Assessed brain hyperconnectivity and social-cognitive behaviors, noting male specificity.

Main Results:

• Mice with *Aspm* gain-of-function mutation exhibited macrocephaly and excessive embryonic neurogenesis.
• An increased E-I ratio and brain hyperconnectivity were observed.
• Male mice displayed social-cognitive deficits.

Conclusions:

• Macrocephaly in ASD is associated with an altered E-I neuronal ratio, rather than a proportional increase in all neuron types.
• The *ASPM* gene mutation influences cortical development, leading to macrocephaly and ASD-like phenotypes.
• Macrocephaly itself may contribute to a subset of ASD-like symptoms, independent of specific gene expression patterns.