title: Glycine transporter 1 is a target for the treatment of epilepsy.
abstract: 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.
authors: Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR 97232, USA.
authors: Hai-Ying
authors: HY
authors: Shen
authors: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, The Netherlands.
authors: Erwin A
authors: EA
authors: van Vliet
authors: Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR 97232, USA.
authors: Kerry-Ann
authors: KA
authors: Bright
authors: Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR 97232, USA.
authors: Marissa
authors: M
authors: Hanthorn
authors: Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR 97232, USA.
authors: Nikki K
authors: NK
authors: Lytle
authors: Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, The Netherlands.
authors: Jan
authors: J
authors: Gorter
authors: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, The Netherlands; Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, The Netherlands; SEIN - Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands.
authors: Eleonora
authors: E
authors: Aronica
authors: Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR 97232, USA. Electronic address: dboison@downeurobiology.org.
authors: Detlev
authors: D
authors: Boison
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007608:Kainic Acid; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D004149:Dioxoles; D050487:Glycine Plasma Membrane Transport Proteins; C534343:LY2365109; C493268:SLC6A9 protein, human; C493267:Slc6a9 protein, mouse; C493266:Slc6a9 protein, rat; D007608:Kainic Acid
keywords: Antiepileptic drugs; GlyT1; Glycine transporter 1; Histopathology; Seizures; Temporal lobe epilepsy