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.