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Lack of interferon regulatory factor 3 leads to anxiety/depression-like behaviors through disrupting the balance of neuronal excitation and inhibition in mice

Disrupting the balance of neuronal excitation and inhibition (E/I) is an important pathogenic mechanism of anxiety and depression. Interferon regulatory factor 3 (IRF3) plays a key role in the innate immune response, and activation of IRF3 triggers the expression of type I interferons and downstream...

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Detalles Bibliográficos
Autores principales: Li, Junjie, Pang, Yayan, Du, Yehong, Xia, Lei, Chen, Mulan, Fan, Yepeng, Dong, Zhifang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Chongqing Medical University 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10308133/
https://www.ncbi.nlm.nih.gov/pubmed/37396521
http://dx.doi.org/10.1016/j.gendis.2022.05.003
Descripción
Sumario:Disrupting the balance of neuronal excitation and inhibition (E/I) is an important pathogenic mechanism of anxiety and depression. Interferon regulatory factor 3 (IRF3) plays a key role in the innate immune response, and activation of IRF3 triggers the expression of type I interferons and downstream interferon-stimulated genes, which are associated with anxiety and depression. However, whether IRF3 participates in the pathogenesis of anxiety/depression by regulating E/I balance remains poorly understood. Here, we reported that global knockout (KO) of IRF3 (IRF3(−/−)) significantly increased anxiety/depression-like behaviors, but did not affect normal spatial learning and memory. Compared with wild type (WT) control mice, the E/I balance was disrupted, as reflected by enhanced glutamatergic transmission and decreased GABAergic transmission in the neurons of hippocampal CA1 and medial prefrontal cortex (mPFC) in IRF3-KO mice. Importantly, genetic rescue of IRF3 expression by adeno-associated virus (AAV) was sufficient to alleviate anxiety/depression-like behaviors and restore the neuronal E/I balance in IRF3-KO mice. Taken together, our results indicate that IRF3 is critical in maintaining neuronal E/I balance, thereby playing an essential role in ensuring emotional stability.