PMID- 26302655
OWN - NLM
STAT- MEDLINE
DCOM- 20160830
LR  - 20240324
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Print)
IS  - 0028-3908 (Linking)
VI  - 99
DP  - 2015 Dec
TI  - Glycine transporter 1 is a target for the treatment of epilepsy.
PG  - 554-65
LID - S0028-3908(15)30076-9 [pii]
LID - 10.1016/j.neuropharm.2015.08.031 [doi]
AB  - 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.
CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
FAU - Shen, Hai-Ying
AU  - Shen HY
AD  - Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, 
      OR 97232, USA.
FAU - van Vliet, Erwin A
AU  - van Vliet EA
AD  - Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, 
      The Netherlands.
FAU - Bright, Kerry-Ann
AU  - Bright KA
AD  - Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, 
      OR 97232, USA.
FAU - Hanthorn, Marissa
AU  - Hanthorn M
AD  - Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, 
      OR 97232, USA.
FAU - Lytle, Nikki K
AU  - Lytle NK
AD  - Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, 
      OR 97232, USA.
FAU - Gorter, Jan
AU  - Gorter J
AD  - Swammerdam Institute for Life Sciences, Center for Neuroscience, University of 
      Amsterdam, The Netherlands.
FAU - Aronica, Eleonora
AU  - Aronica E
AD  - 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.
FAU - Boison, Detlev
AU  - Boison D
AD  - Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, 
      OR 97232, USA. Electronic address: dboison@downeurobiology.org.
LA  - eng
GR  - R01 NS065957/NS/NINDS NIH HHS/United States
GR  - R01 NS084920/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150821
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Anticonvulsants)
RN  - 0 (Dioxoles)
RN  - 0 (Glycine Plasma Membrane Transport Proteins)
RN  - 0 (LY2365109)
RN  - 0 (SLC6A9 protein, human)
RN  - 0 (Slc6a9 protein, mouse)
RN  - 0 (Slc6a9 protein, rat)
RN  - SIV03811UC (Kainic Acid)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Animals
MH  - Anticonvulsants/*pharmacology
MH  - Dioxoles/pharmacology
MH  - Disease Models, Animal
MH  - Electric Stimulation
MH  - Epilepsy, Temporal Lobe/*drug therapy/*metabolism
MH  - Female
MH  - Glycine Plasma Membrane Transport Proteins/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Hippocampus/drug effects/metabolism
MH  - Humans
MH  - Kainic Acid
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Middle Aged
MH  - Rats, Sprague-Dawley
MH  - Seizures/drug therapy/metabolism
PMC - PMC4655139
MID - NIHMS719656
OTO - NOTNLM
OT  - Antiepileptic drugs
OT  - GlyT1
OT  - Glycine transporter 1
OT  - Histopathology
OT  - Seizures
OT  - Temporal lobe epilepsy
EDAT- 2015/08/26 06:00
MHDA- 2016/08/31 06:00
PMCR- 2016/12/01
CRDT- 2015/08/26 06:00
PHST- 2015/06/03 00:00 [received]
PHST- 2015/07/27 00:00 [revised]
PHST- 2015/08/19 00:00 [accepted]
PHST- 2015/08/26 06:00 [entrez]
PHST- 2015/08/26 06:00 [pubmed]
PHST- 2016/08/31 06:00 [medline]
PHST- 2016/12/01 00:00 [pmc-release]
AID - S0028-3908(15)30076-9 [pii]
AID - 10.1016/j.neuropharm.2015.08.031 [doi]
PST - ppublish
SO  - Neuropharmacology. 2015 Dec;99:554-65. doi: 10.1016/j.neuropharm.2015.08.031. 
      Epub 2015 Aug 21.