AUTHOR=Pirone Antonella , Alexander Jonathan M. , Koenig Jenny B. , Cook-Snyder Denise R. , Palnati Medha , Wickham Robert J. , Eden Lillian , Shrestha Neha , Reijmers Leon , Biederer Thomas , Miczek Klaus A. , Dulla Chris G. , Jacob Michele H. 

TITLE=Social Stimulus Causes Aberrant Activation of the Medial Prefrontal Cortex in a Mouse Model With Autism-Like Behaviors

JOURNAL=Frontiers in Synaptic Neuroscience

VOLUME=Volume 10 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/synaptic-neuroscience/articles/10.3389/fnsyn.2018.00035

DOI=10.3389/fnsyn.2018.00035

ISSN=1663-3563

ABSTRACT=Autism spectrum disorder (ASD) is a highly prevalent and genetically heterogeneous brain disorder. Developing effective therapeutic interventions requires knowledge of the brain regions that malfunction and how they malfunction during ASD-relevant behaviors. Our study provides insights into brain regions activated by a novel social stimulus and how the activation pattern differs between mice that display autism-like disabilities and control littermates. Adenomatous polyposis coli (APC) conditional knockout (cKO) mice display reduced social interest, increased repetitive behaviors and dysfunction of the β-catenin pathway, a convergent target of numerous ASD-linked human genes. Here, we exposed the mice to a novel social versus non-social stimulus and measured neuronal activation by immunostaining for the protein c-Fos. We analyzed three brain regions known to play a role in social behavior. Compared with control littermates, APC cKOs display excessive activation, as evidenced by an increased number of excitatory pyramidal neurons stained for c-Fos in the medial prefrontal cortex (mPFC), selectively in the infralimbic sub-region.  In contrast, two other social brain regions, the amygdala and piriform cortex show normal levels of neuron activation. Additionally, APC cKOs exhibit increased frequency of miniature excitatory postsynaptic currents (mEPSCs) in layer 5 pyramidal neurons of the infralimbic sub-region.  Further, immunostaining is reduced for the inhibitory interneuron markers parvalbumin and somatostatin in the APC cKO mPFC. Our findings suggest aberrant excitatory-inhibitory balance and activation patterns. As β-catenin is a core pathway in ASD, we identify the infralimbic sub-region of the mPFC as a critical brain region for autism-relevant social behavior.