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

Moreover, synaptic transmission was disrupted in these TIA1-deficiency mice after LPS induction. Mechanistically, Cacna2d1 (a well-known gene associated with depression) was a key TIA1 target based on results of RNA immunoprecipitation sequencing (RIP-Seq) and single-nucleus RNA sequencing (snRNA-seq) in MDD patients. TIA1 bound to Cacna2d1 mRNA and downregulated its expression in neuronal cells.

In contrast, in TIA1CaMKIIα-CKO mice, Cacna2d1 was upregulated in vCA1 neurons, aggravated the depressive-like behaviors. Finally, both chemogenetic activation of excitatory neurons in the vCA1 or pharmacological inhibition of Cacna2d1 effectively rescued the aggravation of depressive-like behaviors. Together, these results reveal a previously unrecognized role of excitatory neuronal TIA1 in vCA1 by suppressing Cacna2d1, which advances our understanding of the molecular mechanism underlying stress-induced depressive symptoms.