Glycine transporter 1 is a target for the treatment of epilepsy. Neuropharmacology 2015 Dec;99:554-65
Date
08/26/2015Pubmed ID
26302655Pubmed Central ID
PMC4655139DOI
10.1016/j.neuropharm.2015.08.031Scopus ID
2-s2.0-84940567617 (requires institutional sign-in at Scopus site) 37 CitationsAbstract
Glycine is the major inhibitory neurotransmitter in brainstem and spinal cord, whereas in hippocampus glycine exerts dual modulatory roles on strychnine-sensitive glycine receptors and on the strychnine-insensitive glycineB site of the N-methyl-D-aspartate receptor (NMDAR). In hippocampus, the synaptic availability of glycine is largely under control of glycine transporter 1 (GlyT1). Since epilepsy is a disorder of disrupted network homeostasis affecting the equilibrium of various neurotransmitters and neuromodulators, we hypothesized that changes in hippocampal GlyT1 expression and resulting disruption of glycine homeostasis might be implicated in the pathophysiology of epilepsy. Using two different rodent models of temporal lobe epilepsy (TLE)--the intrahippocampal kainic acid model of TLE in mice, and the rat model of tetanic stimulation-induced TLE--we first demonstrated robust overexpression of GlyT1 in the hippocampal formation, suggesting dysfunctional glycine signaling in epilepsy. Overexpression of GlyT1 in the hippocampal formation was corroborated in human TLE samples by quantitative real time PCR. In support of a role of dysfunctional glycine signaling in the pathophysiology of epilepsy, both the genetic deletion of GlyT1 in hippocampus and the GlyT1 inhibitor LY2365109 increased seizure thresholds in mice. Importantly, chronic seizures in the mouse model of TLE were robustly suppressed by systemic administration of the GlyT1 inhibitor LY2365109. We conclude that GlyT1 overexpression in the epileptic brain constitutes a new target for therapeutic intervention, and that GlyT1 inhibitors constitute a new class of antiictogenic drugs. These findings are of translational value since GlyT1 inhibitors are already in clinical development to treat cognitive symptoms in schizophrenia.
Author List
Shen HY, van Vliet EA, Bright KA, Hanthorn M, Lytle NK, Gorter J, Aronica E, Boison DAuthor
Nikki K. Lytle PhD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
Animals
Anticonvulsants
Dioxoles
Disease Models, Animal
Electric Stimulation
Epilepsy, Temporal Lobe
Female
Glycine Plasma Membrane Transport Proteins
Hippocampus
Humans
Kainic Acid
Male
Mice, Inbred C57BL
Mice, Transgenic
Middle Aged
Rats, Sprague-Dawley
Seizures
