Drugs targeting synaptic RNA m6A methylation regulate synaptic transmission and plasticity in the rat hippocampus

m6A methylation is the most abundant modification in eukaryotic mRNA and has been implicated in epitranscriptomic regulation of various cellular functions. Recent studies have demonstrated its significance in brain development, neuronal signalling and memory formation; however, the precise mechanisms by which m6A RNA methylation affects synaptic transmission and plasticity in memory-related neuronal circuits remain unclear. Here, we have studied the effects of newly developed pharmacological compounds that target m6A methylation on excitatory synaptic transmission and plasticity in the hippocampus, using a combination of electrophysiological and immunohistological techniques in infant and adult rats. We demonstrate that STM2457, a highly potent catalytic inhibitor of the m6A methyltransferase METTL3, blocks long-term potentiation (LTP) without affecting basal synaptic transmission in area CA1. Moreover, our findings support that LTP in vivo is associated with elevated m6A immunostaining, suggesting that LTP induction triggers METTL3 activation and a subsequent rise in m6A methylation. Interestingly, pharmacological activation of METTL3/14 or inhibition of the m6A demethylase FTO increased synaptic m6A levels in vivo, yet attenuated LTP in adult hippocampal slices. METTL3/14 activation also diminished long-term depression (LTD). These findings align with a model where elevated m6A methylation acts as a stabilizing signal, limiting excessive activity-dependent plasticity of synaptic transmission across development. Furthermore, they add to the growing body of evidence supporting that dysregulation of m6A RNA methylation perturbs synaptic plasticity - the neurobiological foundation of memory - and demonstrate that these processes can be pharmacologically targeted.