Prelimbic Cortical Stimulation with L-methionine Enhances Cognition through Hippocampal DNA Methylation and Neuroplasticity Mechanisms.

Autor:	Poon CH; 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China., Liu Y; 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China., Pak S; 2Department of Neuroscience, City University of Hong Kong, Kowloon, Hong Kong, China., Zhao RC; 3School of Life Sciences, Shanghai University, Shanghai, China., Aquili L; 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.; 4College of Science, Health, Engineering and Education, Discipline of Psychology, Murdoch University, Perth, Australia., Tipoe GL; 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China., Leung GK; 5Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Chan YS; 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China., Yang S; 2Department of Neuroscience, City University of Hong Kong, Kowloon, Hong Kong, China., Fung ML; 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China., Wu EX; 6Department of Electrical and Electronic Engineering, The University of Hong Kong, Hong Kong, China., Lim LW; 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Jazyk:	angličtina
Zdroj:	Aging and disease [Aging Dis] 2023 Feb 01; Vol. 14 (1), pp. 112-135. Date of Electronic Publication: 2023 Feb 01 (Print Publication: 2023).
DOI:	10.14336/AD.2022.0706
Abstrakt:	Declining global DNA methylation and cognitive impairment are reported to occur in the normal aging process. It is not known if DNA methylation plays a role in the efficacy of memory-enhancing therapies. In this study, aged animals were administered prelimbic cortical deep brain stimulation (PrL DBS) and/or L-methionine (MET) treatment. We found that PrL DBS and MET (MET-PrL DBS) co-administration resulted in hippocampal-dependent spatial memory enhancements in aged animals. Molecular data suggested MET-PrL DBS induced DNA methyltransferase DNMT3a-dependent methylation, robust synergistic upregulation of neuroplasticity-related genes, and simultaneous inhibition of the memory-suppressing gene calcineurin in the hippocampus. We further found that MET-PrL DBS also activated the PKA-CaMKIIα-BDNF pathway, increased hippocampal neurogenesis, and enhanced dopaminergic and serotonergic neurotransmission. We next inhibited the activity of DNA methyltransferase (DNMT) by RG108 infusion in the hippocampus of young animals to establish a causal relationship between DNMT activity and the effects of PrL DBS. Hippocampal DNMT inhibition in young animals was sufficient to recapitulate the behavioral deficits observed in aged animals and abolished the memory-enhancing and molecular effects of PrL DBS. Our findings implicate hippocampal DNMT as a therapeutic target for PrL DBS and pave way for the potential use of non-invasive neuromodulation modalities against dementia. Competing Interests: Competing interests The authors declare no competing financial interests. (copyright: © 2022 Poon et al.)
Databáze:	MEDLINE
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