AbstractBackgroundIncreasing evidence links epileptic seizures to neurodegenerative disorders such as Alzheimer’s disease (AD) although the mechanisms underlying this relationship are not fully understood. Ion channels are crucial to the maintenance of intracellular calcium (Ca2+) signaling in the nervous system, and a perturbation in their structure and function could result in both neuropathology and seizures. Moreover, perturbed cellular Ca2+ homeostasis is known to be implicated in AD pathogenesis. Previous studies in the model organism Drosophila have established a connection between mutations linked to temperature‐sensitive (TS) paralysis, which is reminiscent of vertebrate epileptiform behavior, and neurodegeneration. Thus, Drosophila could serve as an excellent model to investigate the molecular mechanisms relating these two conditions.MethodWe performed an unbiased genetic screen to identify mutants that exhibit paralytic behavior at 38°C. We used gene mapping, and DNA sequencing to locate the mutation in the Nckx30C gene. We carried out TS paralysis assays, lifespan analysis, climbing assay and brain histology to look for neurodegeneration, as well as immunohistochemistry to examine synaptic morphology at the larval neuromuscular junction (NMJ). Knockdown using RNAi established the cell‐type specific basis of the TS‐paralytic and neurodegenerative phenotypes.ResultMutant line 426 exhibited TS paralysis and progressive neurodegeneration in comparison to controls. We mapped the mutation to the Nckx30C locus, in the region encoding the predicted ion‐binding domain. In comparison to wild type, 426 flies showed reduced lifespan, impaired climbing and changes in NMJ morphology, indicative of synaptic dysfunction. We found lifespan reduction and early‐onset neurodegeneration in flies carrying two other Nckx30C alleles. Neuron‐ but not glia‐specific knockdown of Nckx30C recapitulates the TS‐paralytic phenotype of 426 flies. Knockdown of Nckx30C in glia and neurons led to early onset climbing defects.ConclusionThe Drosophila Nckx30C gene encodes for a K+‐dependent Na+/Ca2+ exchanger with enriched expression in brain tissue. Nckx30C is homologous to mammalian Solute Carrier Family 24 (SLC24) proteins of which pathophysiological involvement and function in the brain is poorly understood. Our studies of Nckx30C in flies could help to decipher the function of SLC24 proteins in both seizures and neurodegenerative conditions such as AD.