Hyperactivated PTP1B phosphatase in parvalbumin neurons alters anterior cingulate inhibitory circuits and induces autism-like behaviors

Li Zhang,Alexandre F R Stewart,Shelly A Cruz,Hsiao-Huei Chen,Zhaohong Qin,Konrad M Ricke

doi:10.1038/s41467-020-14813-z

Li Zhang, Alexandre F R Stewart + Show 4 more

Open Access

https://doi.org/10.1038/s41467-020-14813-z

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Abstract

Individuals with autism spectrum disorder (ASD) have social interaction deficits and difficulty filtering information. Inhibitory interneurons filter information at pyramidal neurons of the anterior cingulate cortex (ACC), an integration hub for higher-order thalamic inputs important for social interaction. Humans with deletions including LMO4, an endogenous inhibitor of PTP1B, display intellectual disabilities and occasionally autism. PV-Lmo4KO mice ablate Lmo4 in PV interneurons and display ASD-like repetitive behaviors and social interaction deficits. Surprisingly, increased PV neuron-mediated peri-somatic feedforward inhibition to the pyramidal neurons causes a compensatory reduction in (somatostatin neuron-mediated) dendritic inhibition. These homeostatic changes increase filtering of mediodorsal-thalamocortical inputs but reduce filtering of cortico-cortical inputs and narrow the range of stimuli ACC pyramidal neurons can distinguish. Simultaneous ablation of PTP1B in PV-Lmo4KO neurons prevents these deficits, indicating that PTP1B activation in PV interneurons contributes to ASD-like characteristics and homeostatic maladaptation of inhibitory circuits may contribute to deficient information filtering in ASD.

Highlights

Individuals with autism spectrum disorder (ASD) have social interaction deficits and difficulty filtering information
While social interaction increased the number of c-Fos+ neurons in layer 2/3 of the dACC nearly eightfold compared to naive wild-type mice, fewer c-Fos+ neurons were counted in PV-Lmo4KO mice (Fig. 1d)
Our study shows that selective ablation of Lmo[4] in PV interneurons causes ASD-like behaviors

Summary

Introduction

Individuals with autism spectrum disorder (ASD) have social interaction deficits and difficulty filtering information. Inhibitory interneurons filter information at pyramidal neurons of the anterior cingulate cortex (ACC), an integration hub for higher-order thalamic inputs important for social interaction. PV-Lmo4KO mice ablate Lmo[4] in PV interneurons and display ASD-like repetitive behaviors and social interaction deficits. Simultaneous ablation of PTP1B in PVLmo4KO neurons prevents these deficits, indicating that PTP1B activation in PV interneurons contributes to ASD-like characteristics and homeostatic maladaptation of inhibitory circuits may contribute to deficient information filtering in ASD. Individuals with autism spectrum disorder (ASD) have impaired social communication, inflexible and repetitive stereotyped behaviors, and cognitive deficits tied to deficient filtering of task-irrelevant information[1]. Imaging studies reveal altered function at the anterior cingulate cortex (ACC) and aberrant connectivity between the MD thalamus and ACC in ASD subjects during task performance[12,13]

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