Terminal nucleotidyltransferase microRNA A-tailing enzyme regulates excitatory/inhibitory balance in the hippocampus.

One of the posttranscriptional mechanisms regulating the stability of RNA molecules involves the addition of nontemplated nucleotides to their 3' ends, a process known as RNA tailing. To systematically investigate the physiological consequences of terminal nucleotidyltransferase TENT2 absence on RNA 3' end modifications in the mouse hippocampus, we developed a new knockout mouse. Electrophysiological measurements revealed increased excitability in KO hippocampal neurons, and behavioral analyses showed decreased anxiety and improved fear extinction in these mice. At the molecular level, we observed changes in miRNAs' monoadenylation in KO mouse hippocampus, but found no effect of the TENT2 loss on the mRNAs' total poly(A) tail length, as measured by direct nanopore RNA sequencing. Moreover, differential expression analysis revealed transcripts related to synaptic transmission to be downregulated in the hippocampus of knockout mice. These changes may explain the observed behavioral and electrophysiological alterations. Our data thus establish a link between TENT2-dependent miRNA tailing and the balance of inhibitory and excitatory neurotransmission.