CRMP2 in the hippocampus alleviates chronic stress-induced depressive-like behaviours in mice by affecting synaptic function

Abstract

Major depressive disorder (MDD) is a prevalent psychiatric illness and a significant contributor to the global burden of disease. However, the molecular mechanisms underlying depression are complex and have yet to be fully elucidated. Previous studies demonstrated that collapsin response mediator protein 2 (CRMP2) involved in the onset of depression, but its role is unclear yet. To explore the mechanism of CRMP2 in depression and whether it ameliorates depressive-like behaviours by modulating synaptic functions, we manipulate the expression of CRMP2 by adeno-associated virus (AAV) injected into the hippocampal CA1 region and then induced depressive-like behaviour by subjecting the mice to chronic unpredictable mild stress (CUMS). Sucrose preference test (SPT), open field test (OFT), elevated plus maze test (EPM), forced swimming test (FST), and tail suspension test (TST) are utilized to detect behavioral changes. Golgi-Cox staining and electron microscopy were applied to examine alterations in the structure and morphology of neural synapses. Synaptophysin (SYP), synaptophysin 1 (SYN1), growth-associated protein 43 (GAP43), glutamate receptor 2 (GLUR2) and postsynaptic density protein 95 (PSD95) is tested for synaptic function. The proteins interacting with CRMP2 were comprehensively investigated utilizing Immunoprecipitation-Mass Spectrometry (IP-MS) analysis and the direct binding between CRMP2 and PSD95 was validated. In our study, we observed CRMP2 in the hippocampal CA1 region was downregulated following CUMS. Knockdown of CRMP2 resulted in impaired synaptic structure and decreased expression of synapse-associated proteins, accompanied by increased depressive-like behaviour, like anhedonia and hopelessness. Conversely, overexpression of CRMP2 significantly ameliorated behavioural deficits associated with depression and restore the compromised synaptic structure and function. Our findings suggest that CRMP2 exerts a crucial function in modulating depressive-like behaviours by influencing the synaptic structure and function, and it can directly interact with PSD95.