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Pyridox (am) ine 5'-phosphate oxidase (PNPO) is a rate-limiting enzyme in converting dietary vitamin B6 (VB6) to pyridoxal 5'-phosphate (PLP), the biologically active form of VB6 and involved in the synthesis of neurotransmitters including γ-aminobutyric acid (GABA), dopamine, and serotonin. In humans, PNPO mutations have been increasingly identified in neonatal epileptic encephalopathy and more recently also in early-onset epilepsy. Till now, little is known about the neurobiological mechanisms underlying PNPO-deficiency-induced seizures due to the lack of animal models. Previously, we identified a c.95 C&gt;A missense mutation in  sugarlethal  ( sgll )—the  Drosophila  homolog of human  PNPO  ( hPNPO )—and found mutant ( sgll  95 ) flies exhibiting a lethal phenotype on a diet devoid of VB6. Here, we report the establishment of both  sgll  95  and ubiquitous  sgll  knockdown (KD) flies as valid animal models of PNPO-deficiency-induced epilepsy. Both  sgll  95  and  sgll  KD flies exhibit spontaneous seizures before they die. Electrophysiological recordings reveal that seizures caused by PNPO deficiency have characteristics similar to that in flies treated with the GABA antagonist picrotoxin. Both seizures and lethality are associated with low PLP levels and can be rescued by ubiquitous expression of wild-type  sgll  or  hPNPO , suggesting the functional conservation of the PNPO enzyme between humans and flies. Results from cell type-specific  sgll  KD further demonstrate that PNPO in the brain is necessary for seizure prevention and survival. Our establishment of the first animal model of PNPO deficiency will lead to better understanding of VB6 biology, the  PNPO  gene and its mutations discovered in patients, and can be a cost-effective system to test therapeutic strategies.

Pyridox (am) ine 5'-phosphate oxidase deficiency induces seizures in Drosophila melanogaster