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.
This is a preview of subscription content, access via your institution Receive 12 print issues and online access Prices may be subject to local taxes which are calculated during checkout All data needed to evaluate the conclusions in the paper are available in the paper and Supplementary Figs. and Tables. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (https://proteomecentral.proteomexchange.org) via the iProX partner repository [67, 68] with the dataset identifier PXD077630. Further information and requests for resources and reagents should be directed to and will be fulfilled by corresponding authors.
Huang Y, Wang Y, Wang H, Liu Z, Yu X, Yan J, et al. Prevalence of mental disorders in China: a cross-sectional epidemiological study. Lancet Psychiatry. 2019;6:211–24.
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