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Journal article
Prelimbic Cortical Stimulation with L-methionine Enhances Cognition through Hippocampal DNA Methylation and Neuroplasticity Mechanisms
Aging and disease, Vol.14(1), pp.112-135
2023
PMID: 36818556
Abstract
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.
Details
- Title
- Prelimbic Cortical Stimulation with L-methionine Enhances Cognition through Hippocampal DNA Methylation and Neuroplasticity Mechanisms
- Authors/Creators
- C.H. Poon - 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, ChinaYanzhi Liu - 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, ChinaSojeong Pak - 2Department of Neuroscience, City University of Hong Kong, Kowloon, Hong Kong, ChinaRobert Chunhua Zhao - 3School of Life Sciences, Shanghai University, Shanghai, ChinaLuca AquiliG.L. Tipoe - 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, ChinaGilberto Ka-Kit Leung - 5Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaYing-Shing Chan - 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, ChinaSungchil Yang - 2Department of Neuroscience, City University of Hong Kong, Kowloon, Hong Kong, ChinaMan-Lung Fung - 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, ChinaEd Xuekui Wu - 6Department of Electrical and Electronic Engineering, The University of Hong Kong, Hong Kong, ChinaLee Wei Lim - 1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Publication Details
- Aging and disease, Vol.14(1), pp.112-135
- Publisher
- ISOAD
- Identifiers
- 991005562369507891
- Copyright
- © 2022 Poon et al.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.5 Neuroscience
- 1.5.560 Hippocampus
- Web Of Science research areas
- Geriatrics & Gerontology
- ESI research areas
- Clinical Medicine