Ginsenoside Rb1 Ameliorates Working Memory Deficits Via Regulation of Prefrontal Cortical Gabaergic Transmission in MPTP-Treated Mice

Abstract

Background: Working memory impairment is a common non-motor symptom in the progression of Parkinson's disease (PD). Ginsenoside Rb1, an extract from the Ginseng root, has been demonstrated to ameliorate motor deficits and prevent dopaminergic neuron death in PD. However, whether Rb1 can attenuate the PD-associated deficits in working memory and its underlying mechanism of action are still unclear. Methods: Behavioral tests were used to examine the effect of Rb1 on the working memory deficits in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Gamma-aminobutyric acid (GABA)-chemical exchange saturation transfer (CEST) magnetic resonance imaging and electrophysiology were used to identify the effect of Rb1 on the GABA content and GABAergic synaptic transmission in the prefrontal cortex. Immunofluorescence and western blotting were used to explore the expression of the different GABA receptors. Findings: We found that Rb1 attenuated the impairment in spatial working memory in the MPTP mouse model of PD, and this neuroprotective mechanism involved the regulation of prefrontal cortical GABAergic content and transmission. We demonstrated that Rb1 increased GABA content in the prefrontal cortex, and Rb1 prevented the MPTP-induced decrease of presynaptic GABA release and postsynaptic GABA receptor expression and function. Furthermore, Rb1's promotion of GABA current may be associated with the regulation of GABAA receptor trafficking from the postsynaptic density to the membrane, as well as with the modulation of postsynaptic GABAB receptors to enhance GABAA receptor function. Interpretation: Rb1 may serve as a potential drug candidate for the treatment of cognitive impairments in PD. Funding: The National Natural Science Foundation of China (No. 81704130 to YZ, No. 81774377 and No. 81373999 to LW), the Natural Science Foundation of Fujian Province of China (No. 2017J05139 to YZ), the Natural Science Foundation of Guangdong Province of China (No. 2017A030310643 to YZ), the China Postdoctoral Science Foundation (No. 2016M590598 to YZ), the National Key Research and Development Program of China (No. 2016YFC1305903 to LW), and the Program for New Century Excellent Talents in University of Ministry of Education of China (No. NCET-13-0505 to LW). Declaration of Interest: The authors declare no conflicts of interest. Ethical Approval: All experiments were conducted according to the National Institute of Health guidelines on the care and use of animals (NIH Publications No. 8023, revised 1978) and approved by the Institutional Animal Care and Use Committee of Guangzhou Medical University.