The mammalian genome has hundreds of nuclear-encoded tRNAs suggesting functional redundancy. Thus, the disease-causing potential of these genes have been largely overlooked. Interestingly the arginine UCU tRNA gene, n-Tr20, resides in a quantitative trait locus (QTL) controlling seizure threshold in inbred strains of mice. C57BL/6J (B6J) mice have a high seizure threshold relative to most inbred strains. Given that we previously showed that B6J mice have a mutation in n-Tr20 that impairs its processing, dramatically lowering the level of mature arginine UCU tRNAs in the brain, we asked whether levels of n-Tr20 regulate seizure threshold. Indeed, restoration of wild type levels of n-Tr20 in B6J mice lowered seizure threshold, and complete deletion of n-Tr20 in C57BL/6N (B6N) mice increased seizure threshold. n-Tr20 levels altered synaptic transmission and the excitatory/inhibitory balance in the hippocampus, and also modulated spike-wave discharges in a mouse model of human epilepsy.
Loss of n-Tr20 altered translation initiation by activating the integrated stress response and suppressing mTOR signaling, and rapamycin treatment of wild type (B6N) mice resulted in similar synaptic changes as deletion of n-Tr20. Similar alterations of these signaling pathways were observed upon deletion of a highly expressed isoleucine tRNA suggesting that these changes are a conserved response to tRNA loss. Currently we are extending our analysis of potential disease-causing mutations in tRNAs, the cell specific expression of tRNAs, and the mechanisms underlying synaptic changes upon loss of n-Tr20.