Tunicamycin induces depression-like behaviors in male rats, accompanied by initiated chaperon-mediated autophagy and decreased synaptic protein expression in the hippocampus

•Tunicamycin administration induces an endoplasmic reticulum stress model with depression-like behaviors in male rats.•Tunicamycin administration initiates hippocampal chaperon-mediated autophagy in male rats.•Tunicamycin administration reduces the levels of PSD95, SYN, and BDNF in the hippocampus.•Tunicamycin administration activates hippocampal neuroinflammation in male rats.•Chaperon-mediated autophagy may be involved in the development of depression. Endoplasmic reticulum (ER) stress participates in the occurrence and development of depression, but the underlying mechanism is not fully understood. This study aimed to investigate the behavioral performance and intracerebral molecular changes in an ER stress model of male rats. Intrahippocampal injection of tunicamycin (TM) was performed on male rats as a model of ER stress. The body weight was determined, and behavioral tests, including sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST), were performed to evaluate depressive and anxiety-like phenotypes within 8 days after injection. The levels of chaperone-mediated autophagy (CMA), synaptic proteins, and neuroinflammation related factors in this model were measured via real-time quantitative PCR and Western blot analysis. Intrahippocampal injection of TM (2 or 1 μg) induced depression-like behaviors in rats, as indicated by the reduced body weight, sucrose preference in SPT, central time in OFT, and increased immobility time in FST. The mRNA and protein levels of GRP78, ATF4, CHOP, LAMP2A, IL-1β, IL-6, and TNF-α were significantly increased, while the expressions of MEF2D, PSD95, SYN, p-CREB (Ser133), and BDNF were significantly decreased in the hippocampus in the model group compared with the sham group. These results confirmed that intrahippocampal injection of TM was a valid method to induce an ER stress rat model with depression-like behaviors accompanied by decreased synaptic protein expression and neuroinflammation. The alteration in CMA-related proteins in this ER stress depression model indicated the involvement of CMA in the development of depression.