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

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 vs. 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 medial 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 (PV) and somatostatin (SST) 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.

IRSp53 Deletion in Glutamatergic and GABAergic Neurons and in Male and Female Mice Leads to Distinct Electrophysiological and Behavioral Phenotypes

“…Therefore, Irsp53 expression in glutamatergic neurons in the cortex, where Emx1 is strongly expressed, seems to be important for normal social interaction and locomotor activity. This is in line with the well-known importance of the PFC in the regulation of social cognition and interaction, previously reported in studies with human subjects as well as WT and mutant mice carrying ASD-and schizophrenia-related gene mutations (Ernst et al, 1997;Mundy, 2003;Pierce et al, 2004;Carper and Courchesne, 2005;Amodio and Frith, 2006;Gilbert et al, 2008;Rinaldi et al, 2008;Shalom, 2009;Courchesne et al, 2011;Yizhar et al, 2011;Testa-Silva et al, 2012;Liang et al, 2015;Barak and Feng, 2016;Ko, 2017;Selimbeyoglu et al, 2017;Cao et al, 2018;Pirone et al, 2018;Wang et al, 2018Wang et al, , 2019Guo et al, 2019;Lazaro et al, 2019;Phillips et al, 2019;Yoo et al, 2019). .…”

Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits

“…To determine if cerebellar dysfunction affects mPFC activity, we examined the effect of Tsc1 mutation in PCs (PC- Tsc1 mutant mice 5 ) on mPFC activity. We hypothesized that reduced inhibitory output from the mutant cerebellum would result in increased downstream mPFC activity, which would be consistent with previous studies showing that ASD mouse models display elevated mPFC activation in response to social interaction 21 and that elevations in mPFC excitatory activity result in social deficits 22 , 23 . We performed extracellular single-unit recordings in anesthetized animals and found elevated single-unit firing frequency in the left prelimbic (PRL) mPFC of PC- Tsc1 mutant mice ( Fig.…”

Excessive β-Catenin in Excitatory Neurons Results in Reduced Social and Increased Repetitive Behaviors and Altered Expression of Multiple Genes Linked to Human Autism

“…Both of our mouse lines with elevated β-cat, β-cat cOEs, and APC cKOs, display increased dendritic spine density and reductions in parvalbumin mRNA and protein levels. Further, APC cKOs exhibit increased excitation of pyramidal neurons in the medial PFC when presented with a novel social stimulus (Pirone et al, 2018). Preventing the increase in β-cat in APC cKOs (APC/β-cat cKOs) averts the reductions in parvalbumin and corrects the social and repetitive behavioral phenotypes.…”

“…From these 10 ASD-linked genes, we have focused initially on the downregulated gene, pvalb, encoding the calciumbinding protein, parvalbumin, in fast-spiking interneurons. Excitatory/inhibitory imbalance in the PFC has been shown to alter social behaviors (Yizhar et al, 2011), and our previous study of the APC cKO mouse shows a reduced number of parvalbumin-positive cells in the medial PFC, increased c-fos in excitatory neurons in the infralimbic subregion in response to a novel social stimulus and increased mEPSC frequency (Pirone et al, 2018). qPCR and immunoblots show reductions in pvalb mRNA (One-way ANOVA F (3, 12) = 11.07, p = 0.0009; Figure 3B) and protein levels (One-way ANOVA F (3, 12) = 4.1742, p = 0.0306; Figure 3C) in the PFC of both mouse lines with elevated βcat.…”