Mechanisms by Which Macrocephaly Underlies Autism Spectrum Disorder

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.

Grant Number: 5R21HD108696-02
NIH Institute/Center: NIH
Principal Investigator: BYOUNG-IL BAE