Transcranial alternating current stimulation rescues motor deficits in a mouse model of Parkinson's disease via the production of glial cell line-derived neurotrophic factor

Background: Therapeutic effects of transcranial alternating current stimulation (tACS) for treating Parkinson's disease (PD) are limited to modulating abnormally synchronized oscillations; however, longlasting tACS effects may involve non-neuronal mechanisms like the regulation of neurotrophic factors.& nbsp;Objectives/Hypothesis: We investigated whether tACS exerts neuroprotective effects on dopaminergic neurons in a mouse model of PD by regulating endogenous glial cell line-derived neurotrophic factor (GDNF).& nbsp;Methods: Repeated high-definition tACS (HD-tACS, 20 min, 89.1 mA/mm(2)) was administered over the primary motor cortex of C57BL/6J 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. Behavioral tests assessing motor function, immunohistochemistry, western blots, enzyme-linked immunosorbent assays, and flow cytometric analyses were performed to examine suitable tACS conditions and its underlying mechanisms.& nbsp;Results: Stimulation at representative frequencies (theta to gamma; 20-Hz beta frequency, in particular) attenuated motor dysfunction and protected the dopaminergic neurons with increased GDNF production. Beta-frequency (20 Hz) tACS application significantly attenuated motor deficits to levels comparable with those of levodopa treatment. Moreover, beta-frequency tACS induced the survival of dopaminergic neurons in the substantia nigra with upregulated production of endogenous GDNF in striatal parvalbumin-positive interneurons. An inhibitor of the GDNF receptor-associated rearranged during transfection (RET) kinase suppressed most aspects of the tACS-induced behavioral recovery, dopaminergic cell survival, and GDNF production. Beta-frequency tACS activated RET-related survival signaling for dopaminergic neurons in the substantia nigra.& nbsp;Conclusions: Application of tACS over the primary motor cortex may exert protective effects on dopaminergic neurons in the substantia nigra via activation of endogenous GDNF production by striatal parvalbumin-positive interneurons and its survival signaling. (C)& nbsp;2022 The Authors. Published by Elsevier Inc.& nbsp;& nbsp;