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

Li Zhang (), Zhaohong Qin, Konrad M. Ricke, Shelly A. Cruz, Alexandre F. R. Stewart () and Hsiao-Huei Chen ()
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Li Zhang: Ottawa Hospital Research Institute, Neuroscience
Zhaohong Qin: Ottawa Hospital Research Institute, Neuroscience
Konrad M. Ricke: Ottawa Hospital Research Institute, Neuroscience
Shelly A. Cruz: Ottawa Hospital Research Institute, Neuroscience
Alexandre F. R. Stewart: University of Ottawa Heart Institute
Hsiao-Huei Chen: Ottawa Hospital Research Institute, Neuroscience

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14813-z

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