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

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.

 

Comments：

The study investigated the potential role of DNA methylation in memory-enhancing therapies using aged animals treated with prelimbic cortical deep brain stimulation (PrL DBS) and/or L-methionine (MET). The results indicated that the combination of MET and PrL DBS enhanced hippocampal-dependent spatial memory in aged animals. Molecular data suggested that this treatment induced DNA methyltransferase DNMT3a-dependent methylation, upregulated neuroplasticity-related genes, and inhibited the memory-suppressing gene calcineurin in the hippocampus.

Additionally, the study found that MET-PrL DBS activated the PKA-CaMKIIα-BDNF pathway, increased hippocampal neurogenesis, and enhanced dopaminergic and serotonergic neurotransmission. The researchers also established a causal relationship between DNMT activity and the effects of PrL DBS by inhibiting hippocampal DNMT activity in young animals, which recapitulated the behavioral deficits observed in aged animals and abolished the memory-enhancing and molecular effects of PrL DBS.

Overall, the study suggests that hippocampal DNMT is a therapeutic target for PrL DBS and provides a potential avenue for the use of non-invasive neuromodulation modalities in treating dementia.

Related Products

Cat.No.	Product Name	Information
S2821	RG108	RG108 (N-Phthalyl-L-tryptophan) is an inhibitor of DNA methyltransferase with IC50 of 115 nM in a cell-free assay, does not cause trapping of covalent enzymes.

Related Targets

DNA Methyltransferase