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

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 GABAA 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 GABAA loci that were enriched in FOX family motifs. Mechanistically, Terfa physically associates with Foxj3 and attenuates Foxj3-dependent repression of GABAA promoters. These findings define a Terfa-Foxj3-GABAA regulatory axis that links telomere-associated factors to inhibitory control and neuronal excitability in a vertebrate model.