Excitatory neuronal TIA1 in ventral hippocampal CA1 drives antidepressant-like effects via downregulation of Cacna2d1 signaling in mice

Stress is a known risk factor of major depressive disorder (MDD). T cell-restricted intracellular antigen 1 (TIA1) is an RNA-binding protein that regulates mRNA stability and translational repression. However, its roles in MDD remain largely unknown. Here, we found that TIA1 was mainly expressed in neurons and was significantly downregulated in the hippocampus of mice subjected to chronic unpredictable mild stress (CUMS) or lipopolysaccharide (LPS) exposure. Conditional deletion of TIA1 in the central nervous system (CNS) (TIA1 Nestin -CKO mice) aggravated the depressive-like behaviors after LPS or CUMS exposure. Further analyses revealed that TIA1 was primarily localized in CaMKIIα + neurons. Selective deletion of TIA1 in CaMKIIα + neurons of ventral hippocampal CA1 (vCA1), but not in astrocytes, aggravated depressive-like behaviors after LPS or CUMS induction. Moreover, synaptic transmission was disrupted in these TIA1-deficient mice after LPS induction. Mechanistically, by integrating RNA immunoprecipitation sequencing (RIP-seq) data generated from the vCA1 in this study with a published neuronal TIA1 RIP-seq dataset and snRNA-seq data from patients with MDD, we identified Cacna2d1 as a key downstream target of TIA1. RIP-qPCR further confirmed the interaction between TIA1 and Cacna2d1 mRNA, and TIA1 negatively regulated Cacna2d1 expression in neuronal cells. Importantly, genetic or pharmacological suppression of Cacna2d1 effectively rescued the aggravation of depressive-like behaviors in TIA1 CaMKIIα -CKO mice. Collectively, these findings identify a previously unrecognized role of TIA1 in vCA1 excitatory neurons and reveal suppression of Cacna2d1 signaling as a key mechanism underlying its antidepressant-like effects. Working model of excitatory neuronal TIA1 in the ventral hippocampal CA1 driving antidepressant-like effects via downregulation of Cacna2d1 in mice . Under the physiological state, TIA1 is abundantly expressed in CaMKIIα + neurons of the vCA1, where it binds to Cacna2d1 mRNA and mediates translational silencing, thereby maintaining low Cacna2d1 protein levels and normal behaviors. Under the pathological state induced by stress, TIA1 expression is reduced, which relieves TIA1-mediated translational repression of Cacna2d1. Consequently, Cacna2d1 protein levels are increased, contributing to the development of depressive-like behaviors. Furthermore, TIA1 deficiency further amplifies stress-induced Cacna2d1 upregulation, resulting in aggravated depressive-like behaviors in mice.