GATA3 drives chronic stress-induced depressive-like behaviors by reducing hippocampal CA3 pyramidal neuronal activity in male mice.

GATA-binding protein 3 (GATA3), a member of the GATA transcription factor family crucial for cellular development and differentiation, is normally expressed at low levels in mature neurons. However, its pathophysiological role in the brain remains poorly understood. Here, we report that GATA3 is involved in the mechanisms underlying chronic stress-induced depressive-like behaviors. Specifically, GATA3 expression was significantly increased in the hippocampal CA3 region of male mice exposed to established chronic social defeat stress (CSDS) and chronic restraint stress (CRS) models of depression. Intra-CA3 infusion of K-7174, a GATA family inhibitor, or genetic knockdown of GATA3 in CA3 pyramidal neurons (PNs) protected against CSDS and CRS, exerting significant antidepressant-like effects. Conversely, overexpression of GATA3 in CA3 PNs induced depressive-like behaviors in male naïve mice. Mechanistically, GATA3 modulated depressive-like behaviors in male mice by regulating CA3 pyramidal neuronal activity and excitatory synaptic transmission. Our findings demonstrate a novel role for GATA3 in regulating depressive-like behaviors and suggest its potential as a promising target for antidepressant development.