Propofol Alleviates Depression‐Like Behavior and Cognitive Disorder in Learned Helplessness Model Mice via Regulating Synaptic Function

Propofol, an anesthetic known for its safety, efficacy and neuroprotective properties, has potential novel antidepressant effects. However, its specific mechanisms still require further elucidation. Presently, we established a learned helplessness (LH) depression model to investigate the effects of propofol treatment on depression-like impairment. Thirty adult male C57BL/6j mice were randomly divided into three groups: control group (CON), model group (LH), and propofol group (PRO), with 10 mice per group. Behavioral analyses were conducted using weight measurement, sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), and Morris water maze test (MWM). Subsequently, HE staining was performed to examine pathological changes in the hippocampal region. Western blotting was conducted to assess changes in Notch signaling pathway components, synaptic plasticity-related proteins, and proteins in the glutamate system. Immunofluorescence was used to detect expression changes of NICD, SYP, and DCX. Hippocampal glutamate concentration was determined using a glutamate assay kit. Consequently, stressed mice exhibited pronounced depressive behaviors and decreased spatial learning and memory, accompanied by significant neuronal death in the dentate gyrus of the hippocampal region and reduced levels of neuronal regeneration as well as synaptic plasticity. Additionally, glutamate reuptake function was impaired in depression, manifested specifically as increased glutamate concentrations in the hippocampal region and neuronal glutamate transmission levels. Meaningfully, propofol upregulated Notch signaling pathway activity and improved glutamate reuptake function significantly resulting in enhanced adult hippocampal neurogenesis and synaptic plasticity. These findings demonstrated the effectiveness of propofol as a potential antidepressant and contributed to discovering novel antidepressant drugs.