Caspase-1 modulates chronic restraint stress-induced depression and GABAergic dysfunction via regulating GAD67 in the hippocampus

Abstract Major depression disorder (MDD) is a common psychiatric disorder. Both inflammation and GABAergic dysfunction have been implicated in the pathophysiology of MDD. Caspase-1, a classic inflammatory caspase, regulates AMPARs-mediated glutamatergic neurotransmission. However, the role of caspase-1 in chronic stress-induced GABAergic dysfunction remains largely unknown. In this study, we found that serum and hippocampal caspase-1 levels increased significantly in chronic restraint stress (CRS) mice, and a significant negative correlation occurred between levels of caspase-1 and depression-like behaviors. Furthermore, CRS significantly decreased GAD67 mRNA levels and GABAARs-mediated miniature inhibitory postsynaptic currents (mIPSCs) in the hippocampus. Genetic deficiency of caspase-1 not only blocked CRS-induced depression-like behaviors, but also alleviated CRS-induced impairments in GABAergic neurotransmission, including the decreased expression of GAD67 and the amplitude and frequency of mIPSCs. Finally, reexpression of caspase-1 in the hippocampus of Caspase-1-/- mice increased susceptibility to stress-induced anxiety- and depression-like behaviors through inhibiting GAD67 expression and GABAARs-mediated mIPSCs. Our study suggests that CRS dysregulates GABAergic neurotransmission via increasing the levels of caspase-1 in the hippocampus, ultimately leading to depression-like behaviors. This work illustrates that targeting caspase-1 may provide potential therapeutic benefits to stress-related GABAergic dysfunction in the pathogenesis of MDD.