Activation of glycine receptors modulates spontaneous epileptiform activity in the immature rat hippocampus

Abstract

Key pointsr Taurine has a pro-and anticonvulsive effect on the immature hippocampus, depending on the dose.r The taurine effect is mediated by GABA A and glycine receptors. r The taurine effect can be partially mimicked by glycine. r Inhibition of glycine receptors has a weak proconvulsive effect on the immature hippocampus. r We conclude that an endogenous activation of glycine receptors by glycine or taurine contributed to the control of neuronal excitability in the immature hippocampus.Abstract While the expression of glycine receptors in the immature hippocampus has been shown, no information about the role of glycine receptors in controlling the excitability in the immature CNS is available. Therefore, we examined the effect of glycinergic agonists and antagonists in the CA3 region of an intact corticohippocampal preparation of the immature (postnatal days 4-7) rat using field potential recordings. Bath application of 100 μM taurine or 10 μM glycine enhanced the occurrence of recurrent epileptiform activity induced by 20 μM 4-aminopyridine in low Mg 2+ solution. This proconvulsive effect was prevented by 3 μM strychnine or after incubation with the loop diuretic bumetanide (10 μM), suggesting that it required glycine receptors and an active NKCC1-dependent Cl − accumulation. Application of higher doses of taurine (ࣙ1 mM) or glycine (100 μM) attenuated recurrent epileptiform discharges. The anticonvulsive effect of taurine was also observed in the presence of the GABA A receptor antagonist gabazine and was attenuated by strychnine, suggesting that it was partially mediated by glycine receptors. Bath application of the glycinergic antagonist strychnine (0.3 μM) induced epileptiform discharges. We conclude from these results that in the immature hippocampus, activation of glycine receptors can mediate both pro-and anticonvulsive effects, but that a persistent activation of glycine receptors is required to suppress epileptiform activity. In summary, our study elucidated the important role of glycine receptors in the control of neuronal excitability in the immature hippocampus.R. Chen and A. Okabe contributed equally to this publication.

Glycine transporter 1 is a target for the treatment of epilepsy

“…In patients with temporal lobe epilepsy changes in hippocampal glycine receptor expression have been reported, suggesting dysregulation of glycinergic signaling in epilepsy (Eichler et al, 2008). In line with those findings activation of glycine receptors modulated spontaneous epileptiform activity in the immature rat hippocampus (Chen et al, 2014), whereas GlyT1 inhibitors demonstrated anticonvulsant properties in a rat maximal electroshock test (Kalinichev et al, 2010). However, the role of GlyT1 in human epilepsy and in clinically relevant rodent models of chronic epilepsy has not been studied to date.…”

“…Glycine in the hippocampus combines unique properties to regulate network excitability through opposing roles of pre- and postsynaptic GlyRs (Chen et al, 2014; Eichler et al, 2008; Kirchner et al, 2003; Kubota et al, 2010; Winkelmann et al, 2014), and through activation of the glycine B site of the NMDAR (Black et al, 2009; Labrie and Roder, 2010; Mohler et al, 2008). Therefore, maintenance of glycine homeostasis might play a critical role in epilepsy.…”

“…Importantly, and in contrast to direct NMDAR agonism, the allosteric modulation of NMDARs through activation of the glycine B site does not bear risks for seizure generation or neurotoxicity (Yang and Svensson, 2008). (ii) Low concentrations of extracellular glycine (10 μM) activate presynaptic glycine receptors (GlyRs) and thereby promote pro-convulsant mechanisms (Chen et al, 2014; Kubota et al, 2010; Winkelmann et al, 2014). (iii) Under higher extracellular concentrations (100 μM) glycine binds to extrasynaptic GlyRs in the postsynaptic compartment providing tonic suppression of network excitability (Eichler et al, 2008; Kirchner et al, 2003).…”

The Vigabatrin Induced Retinal Toxicity is Associated with Photopic Exposure and Taurine Deficiency: An In Vivo Study

“…Given the critical role of taurine in the retinal excitability, several researchers have proposed the supplements of taurine-rich foods to suppress the VGB -induced retinal lesions [40,41]. As the anti-epileptic activity of taurine has also been described [42], it is conceivable that the combined use of taurine and VGB might allow for a reduced VGB dosage to minimize side effects such as the retinal toxicity. Herein, the successful preservation of visual function and retinal structure can be achieved in the VGB administered mice by taurine supplements.…”

RNA Editing—Systemic Relevance and Clue to Disease Mechanisms?

“…However, even if GlyRs are expressed at both presynaptic and postsynaptic sites, a small number of presynaptic RNA-edited gain-of-function GlyRs even a single cluster of the non-RNA-edited GlyR α3L splice variant, which contains up to 200 receptor channels (Notelaers et al, 2012), will have a greater impact on the presynaptic membrane potential due to the much smaller volume and hence electrical capacity of this compartment compared to the somatodendritic compartment (Meier et al, 2014). Notably in this context, application of a low glycine concentration (10 μM) to hippocampal slice preparations enhanced the occurrence of epileptiform activity whereas a high glycine concentration (100 μM) attenuated recurrent epileptiform discharge (Chen et al, 2014). These divergent effects can be explained by preponderant functional impact of low glycine on presynaptic GlyRs expressed at glutamatergic terminals, resulting in facilitated glutamate release, and massive recruitment of somatodendritic GlyR activation by 100 μM glycine, resulting in tonic inhibition, respectively.…”