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

Luye Qin; Kaijie Ma; Zhen Yan

doi:10.1016/j.isci.2019.06.014

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

iScience. 2019 Jul 26:17:24-35. doi: 10.1016/j.isci.2019.06.014. Epub 2019 Jun 11.

Authors

Luye Qin¹, Kaijie Ma¹, Zhen Yan²

Affiliations

¹ Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
² 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.

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.

Abstract

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