Repetitive transcranial magnetic stimulation induced changes of N6-methyladenosine modified mRNAs

Repetitive transcranial magnetic stimulation (rTMS) is a widely used method of non-invasive brain stimulation in both research and clinical settings, aimed at inducing synaptic plasticity and targeting conditions like pharmaco-resistant depression and post-traumatic stress disorder. However, the detailed molecular mechanisms underlying rTMS-induced plasticity remain not well understood. N6-methyladenosine (m6A) is the most prevalent modification in the human transcriptome. m6A is known for its reversible nature and thus is a prime candidate for modulating synaptic plasticity via gene expression. This study explored the connection between rTMS-induced synaptic changes and differentially m6A-modified mRNAs in mouse entorhino-hippocampal cultures using m6A-arrays, MeRIP-seq, and direct RNA sequencing. Our results show that ~15% of the transcripts undergo differential methylation, predominantly hypermethylation, 3 hours after rTMS. This was corroborated by immunostainings in human cortical tissue stimulated ex vivo, linking hypermethylation to key processes like glutamatergic neurotransmission and dendritic spine plasticity. Electron microscopy further confirmed morphological changes in spine apparatus organelles. These results highlight m6A mRNA modification upregulation as a crucial component of rTMS-induced synaptic plasticity, offering insights into its molecular mechanisms.