S-nitrosylation of GAD65 is implicated in decreased GAD activity and oxygen-induced seizures.

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2017-07

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Abstract

Breathing oxygen at partial pressures ≥2.5 atmospheres absolute, which can occur in diving and hyperbaric oxygen (HBO2) therapy, can rapidly become toxic to the central nervous system (CNS). This neurotoxicity culminates in generalized EEG epileptiform discharges, tonic-clonic convulsions and ultimately death. Increased production of neuronal nitric oxide (NO) has been implicated in eliciting hyperoxic seizures by altering the equilibrium between glutamatergic and GABAergic synaptic transmission. Inhibition of glutamic acid decarboxylase (GAD) activity in HBO2 promotes this imbalance; however, the mechanisms by which this occurs is unknown. Therefore, we conducted a series of experiments using mice, a species that is highly susceptible to CNS oxygen toxicity, to explore the possibility that NO modulates GABA metabolism. Mice were exposed to 100% oxygen at 4 ATA for various durations, and brain GAD and GABA transaminase (GABA-T) activity, as well as S-nitrosylation of GAD65 and GAD67 were determined. HBO2 inhibited GAD activity by 50% and this was negatively correlated with S-nitrosylation of GAD65, whereas GABA-T activity and S-nitrosylation of GAD67 were unaltered. These results suggest a new mechanism by which NO alters GABA metabolism, leading to neuroexcitation and seizures in HBO2.

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10.1016/j.neulet.2017.05.067

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Gasier, Heath G, Ivan T Demchenko, Lynn G Tatro and Claude A Piantadosi (2017). S-nitrosylation of GAD65 is implicated in decreased GAD activity and oxygen-induced seizures. Neuroscience letters, 653. pp. 283–287. 10.1016/j.neulet.2017.05.067 Retrieved from https://hdl.handle.net/10161/24104.

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