FTSJ1-DEPENDENT TRNA METHYLATION REGULATES INTRINSIC EXCITABILITY OF HIPPOCAMPAL PYRAMIDAL NEURONS

Ftsj1 is an X-linked gene encoding a transfer RNA (tRNA) 2’O-methyltransferase, which catalyzes ribose methylation at positions 32 and 34 on a subset of tRNAs. Loss-of-function mutations in Ftsj1 have been identified in patients with mild to moderate Intellectual Disability (ID), implicating impaired tRNA modification as a molecular pathway contributing to ID pathogenesis. Despite its ubiquitous expression, FTSJ1 loss-of-function results in a surprisingly restricted phenotype, with affected individuals showing predominantly cognitive impairment in the absence of major systemic or motor abnormalities. This raises an important question: Why does the loss of tRNA methylation at positions 32 and 34 mainly affect the brain and not other organs? While current research in the field of genetics is focused on understanding effects of this mutation on tRNA stability and translation efficiency, little is known about the role of the tRNA methyltransferase FTSJ1 in the brain. To address this gap, we used an Ftsj1 knock-out mouse model and analyzed intrinsic excitability of hippocampal CA1 pyramidal neurons using whole-cell patch-clamp electrophysiology. Preliminary results suggest that the Ftsj1 loss-of-function altered intrinsic excitability, resulting in decreased firing frequency, stronger spike-frequency adaptation, and changes in action potential kinetics, including a faster rise time and increased amplitude. These findings suggest disrupted sodium and potassium conductances, and ongoing analyses are currently being conducted to investigate this hypothesis. Together, our findings identify FTSJ1-dependent tRNA methylation as a key regulator of CA1 pyramidal neuron function and suggest that disrupted post-transcriptional modifications might contribute to cognitive deficits through hippocampal circuit impairment.