Terfa Safeguards GABAergic Inhibition and Neuronal Excitability in Zebrafish Through a Foxj3-Linked Transcriptional...

Neuronal hyperexcitability often results from impaired inhibition; however, the upstream regulators of GABAergic gene programs remain unclear. We identified a role for terfa, the zebrafish ortholog of human TERF2, in maintaining inhibitory tone and network stability. Homozygous terfa mutant larvae exhibit microcephaly, behavioral hyperactivity, and abnormal neuronal calcium dynamics, indicating a hyperexcitable state. Transcriptomic and RT-qPCR analyses showed coordinated downregulation of multiple GABA_A receptor subunit genes, accompanied by reduced gad1b reporter activity in the optic tectum. Pharmacological enhancement of inhibition with etomidate or valproic acid alleviated seizure-like behaviors and normalized calcium activity, supporting impaired inhibition as a major contributor to neuronal hyperexcitability. Integrative ATAC-seq and RNA-seq analyses suggested altered chromatin accessibility near GABA_A loci that were enriched in FOX family motifs. Mechanistically, Terfa physically associates with Foxj3 and attenuates Foxj3-dependent repression of GABA_A promoters. These findings define a Terfa-Foxj3-GABA_A regulatory axis that links telomere-associated factors to inhibitory control and neuronal excitability in a vertebrate model.