Increased Homer1-mGluR5 Mediates Chronic Stress-induced Depressive-like Behaviors and Glutamatergic Dysregulation Via Activation of PERK-eIF2α

Glutamatergic dysregulation has served as one common pathophysiology of major depressive disorder (MDD) and a promising target for treatment intervention. Previous studies implicate neurotransmission via metabotropic glutamate receptors (mGluRs) and Homer1 in stress-induced anhedonia, but the mechanisms have not been well elucidated. In the present study, we used two different animal models of depression, chronic social defeat stress (CSDS) and chronic restraint stress (CRS), to investigate the expression of Homer1 isoforms and functional interaction with mGluRs. We found that chronic stress selectively upregulated the expression of Homer1b/c in the hippocampus, whereas the level of Homer1a was unchanged. Additionally, there was a significant negative correlation between the levels of Homer1-mGluR5 signaling and depressive-like behaviors. Both application of paired-pulse low-frequency stimulation (PP-LFS) and the selective group 1 mGluRs agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) significantly enhanced mGluR-dependent long-term depression (LTD) at CA3-CA1 pyramidal cell synapses in slices from susceptible mice, whereas there was no change in NMDAR-dependent LTD induced by LFS. Furthermore, these effects were associated with the internalization of surface AMPARs in hippocampal pyramidal neurons, including reduced the expression of AMPARs and amplitude of AMPARs-mediated mEPSC. Finally, we found that chronic stress activated the KR-like ER kinase-eukaryotic initiation factor 2α (PERK-eIF2α) signaling pathway, subsequently phosphorylated cAMP response element binding protein (CREB) at the S129 and reduced the BDNF level, eventually leading to the impairment of synaptic transmission and depressive-like behaviors. Therefore, our study suggests that PERK-eIF2α acts as a critical target downstream of Homer1-mGluR5 complex to mediate chronic stress-induced depressive-like behaviors, and highlights them as a potential target for the treatment of mood disorder.