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) (TIA1Nestin-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 TIA1CaMKIIα-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.
This research received no external funding. These authors contributed equally: Danni Chen, Yuhao Luo, Rui Yang. School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China Danni Chen, Yuhao Luo, Rui Yang, Yinfeng Yuan, Zhichao Chen, Jingjing Zhang, Yue Guo, Wei Zhang, Furui Liu, Lin Lin, Weiquan Zeng, Zhenrong Xiong, Yongjie Wang & Zhihui Huang Correspondence to Yongjie Wang or Zhihui Huang.
The authors declare no competing interests. All animal experiments were reviewed and approved by the Laboratory Animal Center of Hangzhou Normal University (Approval No. HSD20210903) and were performed in accordance with the approved institutional protocols and relevant guidelines for the care and use of laboratory animals.
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