Loss of axonal function in maternal immune activation models of autism spectrum disorders

Speaker: John Huguenard, Ph.D.
Affiliation: Professor of Neurology and Neurological Sciences, Neurosurgery, and Molecular and Cellular Physiology, Stanford University School of Medicine

Date: October 10, 2018

Talk title: Loss of axonal function in maternal immune activation models of autism spectrum disorders.

Abstract: Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental syndrome with genetic and environmental risk factors.  Infection during pregnancy is strongly implicated as an environmental factor, with maternal immune activation (MIA) identified in the causative pathway.  However, a mechanistic understanding of MIA-induced alterations in brain function and accompanying social behavior remains elusive.  Here, using an established MIA mouse model, we find that offspring exhibit a profound and persistent impairment in excitability of the medial prefrontal cortex (mPFC) – a major locus of social cognition and ASD pathology.  Specifically, we report novel disorganization of the axon initial segment and blunted transmission along the distal axon.  Transcriptomic analysis identified L1cam deficiency as a likely key mediator of these structural and functional impairments.  Downregulation of L1cam in mPFC was found to reproduce sociability deficits.  These results demonstrate a novel mode of circuit dysfunction in ASD – disrupted axonal signaling – which fundamentally alters the output of mPFC neurons.