Electroacupuncture alleviates cognitive impairment through neuroinflammation suppression, BDNF-TrkB pathway modulation and vHIP-mPFC neural oscillation reorganization in sub-chronic MK-801 treated mice

Schizophrenia-associated cognitive impairment (SCI) represents a core, treatment-resistant symptom of schizophrenia that severely compromises patients’ functional outcomes and quality of life. Although electroacupuncture (EA) exhibits promising neuroregulatory potential for neuropsychiatric disorders, robust clinical evidence confirming its efficacy for SCI remains limited, necessitating further preclinical mechanistic exploration. This study aimed to investigate the efficacy of EA at the Zusanli (ST36) acupoint on cognitive impairment using a sub-chronic MK-801-induced mouse model, and to clarify the underlying neurobiological mechanisms. Behavioral assessments revealed a time-dependent therapeutic effect: EA elevated the novel object recognition (NOR) index at week 1, enhanced the novel location recognition (NLR) performance at week 2, and improved both indices at week 3. Mechanistically, EA increased c-Fos⁺ cells expression in the hippocampus (HIP) and medial prefrontal cortex (mPFC) of SCI model mice. EA also suppressed microglial overactivation and reduced the levels of pro-inflammatory cytokines including IL-1β, IL-6, IL-17 A, and TNF-α in these two core brain regions. Additionally, EA upregulated the expressoin of postsynaptic density protein 95 (PSD-95) and synaptophysin (SYP), modulated the brain-derived neurotrophic factor-tyrosine kinase B (BDNF-TrkB) signaling pathway, and rescued the loss of of dentritic spine density and morphological complexity, which may contribute to improved synaptic plasticity. In vivo extracellular electrophysiological recordings revealed trending elevations in vHIP oscillatory activity and vHIP–mPFC theta–gamma phase-amplitude coupling during cognitive tasks after EA treatment, without reaching statistical significance. Collectively, these multi-level findings suggest that EA-linked cognitive improvements in SCI mice correlate with reduced neuroinflammation, adjusted BDNF–TrkB-associated synaptic plasticity, and partial shifts in vHIP–mPFC functional connectivity. This study provides preclinical evidence supporting EA as a potential non-pharmacological approach for SCI intervention, while highlighting that rigourous clinical trials are still required to confirm its translational efficacy and clinical application value.