Elevated body temperature exacerbates arrhythmia and seizure-like activity in a zebrafish model of Timothy syndrome.

Timothy syndrome (TS) is a multisystem disorder with autistic-like features, seizures and life-threatening arrhythmias. Most TS cases are caused by a de novo missense mutation in the CACNA1C gene that encodes the pore-forming subunit of the voltage-gated L-type calcium channel CaV1.2. Patients show highly variable clinical presentations and survival, which may be impacted by acute episodes of hypoglycemia and respiratory dysfunction. In addition, fever, known to activate CaV1.2 channels, may exacerbate TS, yet its impact is poorly understood. We generated a zebrafish model carrying the homologous cacna1c mutation. These fish exhibited arrhythmias, increased susceptibility to pentylenetetrazole-induced seizures, microcephaly, cerebellar hypotrophy and abnormal GABAergic neuron development. Transcriptomic analysis revealed dysregulated expression of neuropeptides including bdnf and vgf. Notably, elevated water temperature elicited arrhythmia and seizure-like behavior even in overtly normal heterozygotes, implicating fever as a modifiable risk. This model provides a platform for dissecting TS pathophysiology and identifying strategies to mitigate fever-related risk.