Long-term intermittent theta burst stimulation alleviates Parkinson's disease-related cognitive impairment by modulating GluN2B in the dorsal hippocampus

Abstract

Cognitive impairment is one of the typical non-motor symptoms of Parkinson's disease (PD) that severely affects the quality of life of patients. However, limited treatments are currently available, suggesting the urgent need for new therapeutic approaches. Intermittent theta burst stimulation (iTBS), an updated pattern of high-frequency repetitive transcranial magnetic stimulation, can potentially improve cognitive function. However, its efficacy on PD-related cognitive impairment and the mechanism underlying it remain unclear. In this study, we found that unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) impaired hippocampus-dependent memory, decreased the expression of GluN2B at both the total and membrane protein levels, reduced the concentration of intracellular Ca²⁺, and resulted in hyperactive theta power in the dorsal hippocampus (dHip) in rats. Fourteen days of iTBS treatment improved the impaired hippocampus-dependent memory in the lesioned rats, which could last for at least 10 days. In addition, iTBS treatment up-regulated the expression of GluN2B at total and membrane protein levels, elevated intracellular Ca²⁺ concentration, and normalized the aberrantly high theta power in the dHip. Furthermore, iTBS treatment failed to improve hippocampus-dependent memory and normalize the aberrant theta power after knocking down the hippocampal GluN2B. Collectively, these findings suggest that 14-day iTBS treatment alleviates hippocampus-dependent memory impairment in PD, which is achieved by up-regulating the expression of the GluN2B, followed by increasing the level of intracellular Ca²⁺ concentration and normalizing hyperactive theta rhythm in the dHip.