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Jul 26, 2019;17 24-35.

Chemogenetic Activation of Prefrontal Cortex in Shank3-Deficient Mice Ameliorates Social Deficits, NMDAR Hypofunction, and Sgk2 Downregulation.

Luye Qin, Kaijie Ma, Zhen Yan
Author Information
  1. Luye Qin: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
  2. Kaijie Ma: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
  3. Zhen Yan: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA. Electronic address: zhenyan@buffalo.edu.
PMID: 31247448 DOI: 10.1016/j.isci.2019.06.014

Abstract

Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorders (ASDs) in human genetic studies. Here we found that chemogenetic activation of pyramidal neurons in the prefrontal cortex (PFC) of Shank3-deficient mice with the hM3D (Gq) DREADD restored social preference behaviors and elevated glutamatergic synaptic function in PFC. Moreover, the expression of Sgk2 (serum- and glucocorticoid-inducible kinase 2), a member of the Sgk family, which plays a key role in regulating the membrane trafficking of glutamate receptors, was diminished by Shank3 deficiency and rescued by Gq DREADD activation of PFC. Blocking Sgk function in Shank3-deficient mice prevented Gq DREADD from rescuing social and synaptic deficits, whereas blocking Sgk function in wild-type mice led to the attenuation of PFC glutamatergic signaling and the induction of autism-like social deficits. These results have provided a potential circuit intervention and molecular target for autism treatment.

Keywords

Behavioral Neuroscience Cellular Neuroscience Molecular Neuroscience Neuroscience

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Grants

  1. R01 DA037618/NIDA NIH HHS
  2. R01 MH108842/NIMH NIH HHS
  3. R03 MH116453/NIMH NIH HHS
  4. R41 MH112237/NIMH NIH HHS
Journal Article
Article has an altmetric score of 2

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