Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder

Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Daniel A. Nagode, Xiangying Meng, Daniel E. Winkowski, Ed Smith, Hamza Khan-Tareen, Vishnupriya Kareddy, Joseph P.Y. Kao, Patrick O. Kanold
Autism spectrum disorder (ASD) involves deficits in speech and sound processing. Cortical circuit changes during early development likely contribute to such deficits. Subplate neurons (SPNs) form the earliest cortical microcircuits and are required for normal development of thalamocortical and intracortical circuits. Prenatal valproic acid (VPA) increases ASD risk, especially when present during a critical time window coinciding with SPN genesis. Using optical circuit mapping in mouse auditory cortex, we find that VPA exposure on E12 altered the functional excitatory and inhibitory connectivity of SPNs. Circuit changes manifested as "patches" of mostly increased connection probability or strength in the first postnatal week and as general hyper-connectivity after P10, shortly after ear opening. These results suggest that prenatal VPA exposure severely affects the developmental trajectory of cortical circuits and that sensory-driven activity may exacerbate earlier, subtle connectivity deficits. Our findings identify the subplate as a possible common pathophysiological substrate of deficits in ASD.

Graphical abstract

Teaser

It has been hypothesized that dysfunction of subplate neurons is an early event in autism pathology, but never directly tested. Nagode et al. demonstrate spatially restricted increases in excitatory and inhibitory connectivity to subplate in the VPA autism model. These results provide direct evidence of subplate dysfunction in autism.


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