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Deletion of the betaine-GABA transporter (BGT1; slc6a12) gene does not affect seizure thresholds of adult mice

Lehre, A C ; Rowley, N M ; Zhou, Y LU ; Holmseth, S ; Guo, C LU ; Holen, T ; Hua, R ; Laake, P ; Olofsson, A M and Poblete-Naredo, I , et al. (2011) In Epilepsy Research 95(1-2). p.70-81
Abstract

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. Once released, it is removed from the extracellular space by cellular uptake catalyzed by GABA transporter proteins. Four GABA transporters (GAT1, GAT2, GAT3 and BGT1) have been identified. Inhibition of the GAT1 by the clinically available anti-epileptic drug tiagabine has been an effective strategy for the treatment of some patients with partial seizures. Recently, the investigational drug EF1502, which inhibits both GAT1 and BGT1, was found to exert an anti-convulsant action synergistic to that of tiagabine, supposedly due to inhibition of BGT1. The present study addresses the role of BGT1 in seizure control and the effect of EF1502 by... (More)

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. Once released, it is removed from the extracellular space by cellular uptake catalyzed by GABA transporter proteins. Four GABA transporters (GAT1, GAT2, GAT3 and BGT1) have been identified. Inhibition of the GAT1 by the clinically available anti-epileptic drug tiagabine has been an effective strategy for the treatment of some patients with partial seizures. Recently, the investigational drug EF1502, which inhibits both GAT1 and BGT1, was found to exert an anti-convulsant action synergistic to that of tiagabine, supposedly due to inhibition of BGT1. The present study addresses the role of BGT1 in seizure control and the effect of EF1502 by developing and exploring a new mouse line lacking exons 3-5 of the BGT1 (slc6a12) gene. The deletion of this sequence abolishes the expression of BGT1 mRNA. However, homozygous BGT1-deficient mice have normal development and show seizure susceptibility indistinguishable from that in wild-type mice in a variety of seizure threshold models including: corneal kindling, the minimal clonic and minimal tonic extension seizure threshold tests, the 6Hz seizure threshold test, and the i.v. pentylenetetrazol threshold test. We confirm that BGT1 mRNA is present in the brain, but find that the levels are several hundred times lower than those of GAT1 mRNA; possibly explaining the apparent lack of phenotype. In conclusion, the present results do not support a role for BGT1 in the control of seizure susceptibility and cannot provide a mechanistic understanding of the synergism that has been previously reported with tiagabine and EF1502.

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keywords
Animals, Anticonvulsants/therapeutic use, Convulsants/toxicity, Crosses, Genetic, Dose-Response Relationship, Drug, Electroshock/adverse effects, Exons/genetics, Female, GABA Plasma Membrane Transport Proteins/deficiency, Isoxazoles/therapeutic use, Kindling, Neurologic/drug effects, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nipecotic Acids/therapeutic use, Pentylenetetrazole/toxicity, RNA, Messenger/biosynthesis, Seizures/chemically induced
in
Epilepsy Research
volume
95
issue
1-2
pages
70 - 81
publisher
Elsevier
external identifiers
  • pmid:21459558
  • scopus:79957936782
ISSN
1872-6844
DOI
10.1016/j.eplepsyres.2011.02.014
language
English
LU publication?
no
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5de6d540-f3ce-41a6-9004-ae605bebf627
date added to LUP
2018-08-27 14:03:16
date last changed
2020-06-10 05:36:59
@article{5de6d540-f3ce-41a6-9004-ae605bebf627,
  abstract     = {<p>Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. Once released, it is removed from the extracellular space by cellular uptake catalyzed by GABA transporter proteins. Four GABA transporters (GAT1, GAT2, GAT3 and BGT1) have been identified. Inhibition of the GAT1 by the clinically available anti-epileptic drug tiagabine has been an effective strategy for the treatment of some patients with partial seizures. Recently, the investigational drug EF1502, which inhibits both GAT1 and BGT1, was found to exert an anti-convulsant action synergistic to that of tiagabine, supposedly due to inhibition of BGT1. The present study addresses the role of BGT1 in seizure control and the effect of EF1502 by developing and exploring a new mouse line lacking exons 3-5 of the BGT1 (slc6a12) gene. The deletion of this sequence abolishes the expression of BGT1 mRNA. However, homozygous BGT1-deficient mice have normal development and show seizure susceptibility indistinguishable from that in wild-type mice in a variety of seizure threshold models including: corneal kindling, the minimal clonic and minimal tonic extension seizure threshold tests, the 6Hz seizure threshold test, and the i.v. pentylenetetrazol threshold test. We confirm that BGT1 mRNA is present in the brain, but find that the levels are several hundred times lower than those of GAT1 mRNA; possibly explaining the apparent lack of phenotype. In conclusion, the present results do not support a role for BGT1 in the control of seizure susceptibility and cannot provide a mechanistic understanding of the synergism that has been previously reported with tiagabine and EF1502.</p>},
  author       = {Lehre, A C and Rowley, N M and Zhou, Y and Holmseth, S and Guo, C and Holen, T and Hua, R and Laake, P and Olofsson, A M and Poblete-Naredo, I and Rusakov, D A and Madsen, K K and Clausen, R P and Schousboe, A and White, H S and Danbolt, N C},
  issn         = {1872-6844},
  language     = {eng},
  number       = {1-2},
  pages        = {70--81},
  publisher    = {Elsevier},
  series       = {Epilepsy Research},
  title        = {Deletion of the betaine-GABA transporter (BGT1; slc6a12) gene does not affect seizure thresholds of adult mice},
  url          = {http://dx.doi.org/10.1016/j.eplepsyres.2011.02.014},
  doi          = {10.1016/j.eplepsyres.2011.02.014},
  volume       = {95},
  year         = {2011},
}