Mettl14 Is Essential for Epitranscriptomic Regulation of Striatal Function and Learning.

N6 -methyladenosine (m6 A) regulates mRNA metabolism and translation, serving as an important source of post-transcriptional regulation. To date, the functional consequences of m6 A deficiency within the adult brain have not been determined. To achieve m6 A deficiency, we deleted Mettl14, an essential component of the m6 A methyltransferase complex, in two related yet discrete mouse neuronal populations: striatonigral and striatopallidal. Mettl14 deletion reduced striatal m6 A levels without altering cell numbers or morphology. Transcriptome-wide profiling of m6 A-modified mRNAs in Mettl14-deleted striatum revealed downregulation of similar striatal mRNAs encoding neuron- and synapse-specific proteins in both neuronal types, but striatonigral and striatopallidal identity genes were uniquely downregulated in each respective manipulation. Upregulated mRNA species encoded non-neuron-specific proteins. These changes increased neuronal excitability, reduced spike frequency adaptation, and profoundly impaired striatal-mediated behaviors. Using viral-mediated, neuron-specific striatal Mettl14 deletion in adult mice, we further confirmed the significance of m6 A in maintaining normal striatal function in the adult mouse.