HINT1 in ventral hippocampal GABAergic neurons mediates depressive-like behaviors

Depression is a complex psychiatric disorder with multifaceted etiologies, and its underlying molecular mechanisms are incompletely elucidated. Although histidine trimeric nucleotide-binding protein 1 (HINT1) has been implicated in major depressive disorders (MDD), its precise role and regulatory mechanism remain unclear. This study investigated the role of HINT1 in depression-associated phenotypes. In mice subjected to chronic social defeat stress (CSDS), stress-susceptible individuals exhibited significant upregulation of HINT1 in the hippocampus and medial prefrontal cortex. Targeted overexpression of HINT1 in ventral hippocampus (vHip) demonstrated that HINT1 directly induced depressive-like behaviors, whereas its knockdown exerted a robust antidepressant-like effect. Pharmacological inhibition of HINT1 with the selective inhibitor Tryptamine guanosine carbamate (TpGc) in vHip also reversed behavioral deficits and normalized neuronal activity in the CSDS-exposed mice. Cell-type-specific analyses demonstrated that HINT1 overexpression in vHip GABAergic neurons, including somatostatin-positive (SST⁺) and parvalbumin-positive (PV⁺) subtypes, exacerbated depressive-like phenotypes and disrupted neuronal activity. Proteomics analysis identified that HINT1 overexpression in the vHip significantly upregulated the small ubiquitin-like modifier (SUMO) E3 ligases chromobox 4 (CBX4). Further overexpression of CBX4 in the GABAergic neurons of vHip induced depressive-like behaviors. Mechanistically, HINT1 interacted with and inhibited the phosphorylation of protein kinase C-β1 (PKCβ1), suppressing its downstream MEK1/2-ERK1/2 signaling and thereby increasing CBX4 levels. CBX4 promoted the SUMOylation of the glutamate N-methyl-D-aspartate receptor subunit 2 A (GluN2A) and affected its phosphorylation and trafficking. These findings demonstrated HINT1 as a key regulator of GABAergic signaling in vHip and highlighted its therapeutic potential for depression.