Deletion of SH2D5 alleviates epileptic seizures and NMDAR expression via autophagic degradation of STAT1
Haokun Guo, Hui Zhang, Chenlu Zhang, Yuanyuan Shen, Liumi Jiang, Min Yang, Yuansong Zhang, Ningning Zhang, Ruirui Zhang, Ran Yu, Yong Yang, Xin Tian
Haokun Guo, Hui Zhang, Chenlu Zhang, Yuanyuan Shen, Liumi Jiang, Min Yang, Yuansong Zhang, Ningning Zhang, Ruirui Zhang, Ran Yu, Yong Yang, Xin Tian
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Research Article Cell biology Neuroscience

Deletion of SH2D5 alleviates epileptic seizures and NMDAR expression via autophagic degradation of STAT1

Abstract

Epilepsy is a common neurological disorder resulting from an imbalance between neuronal excitation and inhibition. Synapses play a pivotal role in the pathogenesis of epilepsy. Src-homology 2 (SH2) domain–containing protein 5 (SH2D5) is highly expressed in the brain and is implicated in the regulation of synaptic function. However, its role and mechanism in epilepsy remain unclear. In this study, we found that SH2D5 was predominantly localized to pyramidal neurons in the mouse hippocampus and was upregulated in the hippocampus of epileptic brains. KO of Sh2d5 in the hippocampus alleviated both the susceptibility to and severity of epileptic activity. Mechanistically, SH2D5 regulated N-methyl-D-aspartate receptor–mediated (NMDAR–mediated) excitatory synaptic transmission by altering the protein expression levels of NMDAR subunits. We further demonstrated that SH2D5 modulated the transcription of NMDARs by promoting the autophagic degradation of STAT1. These findings suggest that targeting the SH2D5/STAT1/NMDAR pathway may offer a potential therapeutic strategy for epilepsy.

Authors

Haokun Guo, Hui Zhang, Chenlu Zhang, Yuanyuan Shen, Liumi Jiang, Min Yang, Yuansong Zhang, Ningning Zhang, Ruirui Zhang, Ran Yu, Yong Yang, Xin Tian

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Figure 6

SH2D5 modulates NMDAR transcript levels via STAT1.

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SH2D5 modulates NMDAR transcript levels via STAT1. (A) KEGG pathway anal...
(A) KEGG pathway analysis of the LC–MS/MS quantitative proteomics data from Sh2d5-KO and control mice with epilepsy. The proteins outlined in red are related to the JAK/STAT signaling pathway. (B) Volcanic map of differentially expressed proteins identified by LC-MS/MS quantitative proteomics. (C) Verification of changes in glutamatergic receptor levels via qPCR. (D and E) Representative Western blot images (D) and quantification (E) of STAT1 and STAT1 dimer levels. (F and G) Representative Western blot images (F) and quantification (G) of p-STAT3-705, p-STAT3-727, and STAT3 levels. (H and I) Representative Western blot images (H) and quantification (I) of the protein levels of NMDARs after inhibition of STAT1 by fludarabine. (J–M) Quantification of the latency to seizure onset (J), latency to SE onset (K), latency to the first SRS (L), and total number of SRSs within 4 weeks (M) after KA treatment. (N) Representative images of LFP recordings taken 5 weeks after KA treatment. (O and P) Quantitative analysis of LFP recordings. (Q) Quantification of PTZ kindling–induced epileptic seizures. The data are presented as mean ± SEM. Unpaired t test in C, E, G, I–M, O, and P; 2-way ANOVA with Tukey’s multiple-comparison test in Q. *P < 0.05, **P < 0.01, and ***P < 0.001.