FAM26F is a novel regulator of depression-related behaviors by modulating hippocampal glutamatergic neuron activity

Major depressive disorder is a leading cause of disability that significantly exacerbates the disease burden worldwide. FAM26F is a calcium homeostasis regulatory protein, and no studies have reported on its expression and function in brain regions involved in emotional regulation. However, the molecular mechanism by which FAM26F is involved in the pathogenesis of depression is unclear. Here, we observed that the FAM26F expression in the hippocampal dentate gyrus (DG) region was significantly downregulated and predominantly localized in glutamatergic neurons. Specific knockdown of FAM26F in glutamatergic neurons within the DG region induced depression-like behaviors in mice, whereas targeted overexpression ameliorated chronic unpredictable stress (CUS)-induced depression-like behaviors. Then, fiber optic recordings indicated that following FAM26F knockout, the neuronal activity of glutamatergic neurons as well as glutamate levels within the DG were decreased. Furthermore, FAM26F modulated glutamate homeostasis by regulating the function of glutamate synthesis, transport and the expression of glutamate receptors. Finally, high-throughput RNA-seq analysis showed that knockdown of FAM26F altered the expression of genes governing synaptic vesicle cycling and transporter complex. Our findings emphasize that FAM26F can regulate depression-related behaviors in mice by influencing the activity of glutamatergic neurons in the DG.