Objective: This study investigated whether electroacupuncture (EA) exerted neuroprotection by regulating the physical coupling of extrasynaptic N-methyl-D-aspartate receptor (NMDAR) to the transient receptor potential (TRP) channel M4 (TRPM4), and explored the involvement of striatal-enriched tyrosine phosphatase 61 (STEP61).

Background: Parkinson’s disease (PD) is characterized by progressive dopaminergic neurodegeneration, with synaptic dysfunction, particularly involving NMDAR mediated glutamate excitotoxicity and pathological α-synuclein aggregation. While EA has demonstrated therapeutic effectiveness in alleviating PD clinical symptoms, its underlying mechanisms, especially concerning the modulation of the excitotoxicity induced by physical coupling of extrasynaptic NMDAR to TRPM4, need to be explored, yet the intrinsic regulatory mechanisms controlling this extrasynaptic NMDAR/TRPM4 complex remain unclear.

Method: After 28-day EA treatment in a 6-hydroxydopamine (6-OHDA)-lesioned PD rat model, animals were subjected to integrated behavioral, neuropathological, electrophysiological, and molecular analyses, augmented by AAV-mediated striatal STEP61 knockdown and overexpression.

Results: Our results showed that EA significantly ameliorated motor and non-motor deficits, preserved dopaminergic neurons, and reduced phosphorylated α-synuclein accumulation. At the synaptic level, EA rescued corticostriatal long-term potentiation (LTP), restored dendritic spine density, and normalized synaptic protein levels. Mechanistically, EA upregulated the striatal expression of STEP61 to reverse a 6-OHDA induced pathological translocation of NMDAR subunits (GluN1, GluN2A, GluN2B) and the transient receptor potential (TRP) channel M4 (TRPM4) to extrasynaptic fraction, which is strongly associated with excitotoxicity. Critically, neuronal knockdown of STEP61 eliminated the therapeutic benefits of EA treatment, whereas neuronal overexpression of STEP61 was sufficient to achieve the correction of receptor localization, restoration of synaptic integrity, and reactivation of the ERK/CREB/BDNF pro-survival pathway.

Conclusion: Taken together, our work demonstrated STEP61 as a critical molecular mediator in EA therapeutic strategy and highlighted its potential as a therapeutic target for developing interventional therapeutics in PD.

« Back to 2026 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/electroacupuncture-restores-cortico-striatal-synaptic-plasticity-by-promoting-step61-against-6-ohda-induced-extrasynaptic-nmdar-trpm4-complex/