Abstract
Mammalian neurons undergo rapid excitotoxic cell death when deprived of oxygen; however, the common goldfish (Carassius auratus) has the unique ability of surviving in oxygen-free waters, under anoxia. This organism utilizes γ-amino butyric acid (GABA) signaling to suppress excitatory glutamatergic activity during anoxic periods. Although GABAA receptor antagonists are not deleterious to the cellular survival, coinhibition of GABAA and GABAB receptors is detrimental by abolishing anoxia-induced neuroprotective mechanisms. Here we show that blocking the anoxic GABAergic neurotransmission induces seizure-like activity (SLA) analogous to a paroxysmal depolarization shift (PDS), with hyperpolarization of action potential (AP) threshold and elevation of threshold currents. The observed PDS was attributed to an increase in excitatory postsynaptic currents (EPSCs) that are normally attenuated with decreasing oxygen levels. Furthermore, for the first time, we show that in addition to PDS, some neurons undergo depolarization block and do not generate AP despite a suprathreshold membrane potential. In conclusion, our results indicate that with severe hypoxia and absence of GABA receptor activity, telencephalic neurons of C. auratus manifest a paroxysmal depolarization shift, a key feature of epileptic discharge.NEW & NOTEWORTHY This work shows that the combination of anoxia and inhibition of GABA receptors induces seizure-like activities in goldfish telencephalic pyramidal and stellate neurons. Importantly, to prevent seizure-like activity, an intact GABA-mediated inhibitory pathway is required.
Highlights
With termination of oxidative phosphorylation due to decreasing oxygen levels, the brain resorts to glycolysis as the only major source of ATP production
We reported that when exposed to severe hypoxia without any pharmacological manipulations, membrane potential of both stellate and pyramidal neurons shift toward a depolarizing GABAA reversal potential (EGABA), inducing an inhibitory shunt in pyramidal cells only; this depolarization sufficiently generates action potentials in the inhibitory stellate cells, suppressing the overall electrical activity of the brain [10]
Similar to Wilkie et al [18], we show that with severe hypoxia, excitatory postsynaptic currents (EPSCs) mediated by a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptors are suppressed in pyramidal neurons
Summary
With termination of oxidative phosphorylation due to decreasing oxygen levels, the brain resorts to glycolysis as the only major source of ATP production. This strategy cannot meet the metabolic demands of neurons, and ATP shortage leads to excitotoxic-cell death [1]. Attenuation of ATP turnover is achieved through a decrease in the neuronal activity via a number of overlapping mechanisms, namely, “channel arrest,” “spike arrest,” and “synaptic arrest” [5,6,7] These strategies aim to reduce energetically demanding neuronal excitation when ATP is scarce and oxidative phosphorylation is not possible
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