METTL14/YTHDC1-mediated m6A modification in hippocampus improves pentylenetetrazol-induced acute seizures

Epilepsy is a common neurological disorder which can cause significant morbidity and mortality. N6-methyladenosine (m6A), the most common chemical epigenetic modification among mRNA post-transcriptional modifications, implicated in various physiological and pathological processes, but its role in epilepsy is still unknown. Here, we provide strong evidences in support of an association of m6A and its regulatory proteins with epilepsy. Our results indicated that the level of m6A was declined in the hippocampus of pentylenetetrazol (PTZ)-induced seizure mice. Both the seizure-like behaviors and the excessive activation of hippocampal neuron were significantly mitigated after the administration of m6A agonist Betaine. Mechanically, we found both the hippocampal m6A methyltransferase METTL14 and recognition protein YTHDC1 were decreased in PTZ kindled mice, which might contribute to the reduced hippocampal m6A level. Additionally, hippocampal-specific over-expression of METTL14 or YTHDC1 by lentivirus injection could significantly ameliorate seizure-like behaviors and prevent the excessive activation of hippocampal neuron in epilepsy mice induced by PTZ injection, which might be due to the normalized hippocampal m6A level. Together, this study identified METTL14/YTHDC1-mediated m6A modification could participate in seizure-like behaviors, which might provide m6A regulation as a potential and novel therapeutic strategy for epilepsy.