Abstracts

Rationale: Glycine is a major inhibitory neurotransmitter in the CNS and an important regulator of hippocampal excitability. Glycine augmentation via inhibition of glycine transporter 1 (GlyT1) emerges as a therapeutic strategy for epilepsy treatment. This study aimed to explore the cellular contribution of GlyT1 inhibition to seizure suppression._x000D_
Methods: Two mouse lines with conditional forebrain-selective deletion of GlyT1 in neurons (CamKIIα-GlyT1 KO) or neurons plus astrocytes (Emx1-GlyT1 KO) and AAV-based viral GlyT1 knockdown approaches were used to evaluate cell-specific effects of GlyT1-inhibition in acute and chronic seizure models - pentylenetetrazole (PTZ) threshold model and intrahippocampal kainic acid (IHKA) epilepsy model. EEG monitory and analysis were used for seizure evaluation. Pharmacological glycine receptor agonist (taurine), an NMDA receptor inhibitor (kynurenic acid), and GlyT1 inhibitors were used for mechanistic evaluation._x000D_
Results: (1) Seizure burden was significantly lower in epileptic Emx1-GlyT1 KOs vs WTs, no seizure reduction was seen in CAMkII-GlyT1 KOs; similarly, (2) Emx1-GlyT1 KOs showed an increased PTZ-seizure threshold vs WTs, but no increase in CamKIIα-KOs; (3) Astrocytic Gfa2-GlyT1 viral knockdown of hippocampal GlyT1 significantly delayed the progression of seizures vs control virus; (4) Single- and repeated-treatment of taurine (300 mg/kg, i.p.) significantly reduced seizure burden in epileptic WT mice, this effect was not seen in epileptic Emx1-GlyT1 KOs; (5) Pretreatment of taurine (300 mg/kg, i.p) increased PTZ-seizure threshold in WTs but not in Emx1-GlyT1 KOs. _x000D_
Conclusions: Our findings suggest a key role of astrocytic GlyT1 on seizure suppression and activation of glycine receptor contributes to GlyT1-mediated seizure suppression. _x000D_
Funding: This work was supported by grants from the NIH (R01NS084920) and the Good Samaritan Foundation of Legacy Health.