Systemic availability of guanidinoacetate affects GABAA receptor function and seizure threshold in GAMT deficient mice.

Details

Serval ID
serval:BIB_BA71A6C0C171
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Systemic availability of guanidinoacetate affects GABAA receptor function and seizure threshold in GAMT deficient mice.
Journal
Amino acids
Author(s)
Schulze A., Tran C., Levandovskiy V., Patel V., Cortez M.A.
ISSN
1438-2199 (Electronic)
ISSN-L
0939-4451
Publication state
Published
Issued date
08/2016
Peer-reviewed
Oui
Volume
48
Number
8
Pages
2041-2047
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Deficiency of guanidinoacetate methyltransferase (GAMT) causes creatine depletion and guanidinoacetate accumulation in brain with the latter deemed to be responsible for the severe seizure disorder seen in affected patients. We studied electrical brain activity and GABAA mediated mechanisms of B6J.Cg-Gamt(tm1Isb) mice. Electrocorticographic (ECoG) monitoring of pharmacological treatments with ornithine (5 % in drinking water for 5-18 days) and/or Picrotoxin (PTX) (a GABAA receptor antagonist) (1.5 mg/kg, I.P.) in Gamt(MUT) and Gamt(WT) groups [n = 3, mean age (SEM) = 6.9 (0.2) weeks]. Mice were fitted with two frontal and two parietal epidural electrodes under ketamine/xylazine anesthesia. Baseline and test recordings were performed for determination of seizure activity over a 2 h period. The ECoG baseline of Gamt(MUT) exhibited an abnormal monotonous cortical rhythm (7-8 Hz) with little variability during awake and sleep states compared to wild type recordings. Ornithine treatment and also PTX administration led to a relative normalization of the Gamt(MUT) ECoG phenotype. Gamt(WT) on PTX exhibited electro-behavioral seizures, whereas the Gamt(MUT) did not have PTX induced seizures at the same PTX dose. Gamt(MUT) treated with both ornithine and PTX did not show electro-behavioral seizures while ornithine elevated the PTX seizure threshold of Gamt(MUT) mice even further. These data demonstrate: (1) that there is expression of electrical seizure activity in this Gamt-deficient transgenic mouse strain, and (2) that the systemic availability of guanidinoacetate affects GABAA receptor function and seizure thresholds. These findings are directly and clinically relevant for patients with a creatine-deficiency syndrome due to genetic defects in GAMT and provide a rational basis for a combined ornithine/picrotoxin therapeutic intervention.

Keywords
Animals, Electrocorticography, Glycine/analogs & derivatives, Glycine/pharmacokinetics, Glycine/pharmacology, Guanidinoacetate N-Methyltransferase/deficiency, Guanidinoacetate N-Methyltransferase/metabolism, Language Development Disorders/metabolism, Language Development Disorders/pathology, Language Development Disorders/physiopathology, Mice, Mice, Knockout, Movement Disorders/congenital, Movement Disorders/metabolism, Movement Disorders/pathology, Movement Disorders/physiopathology, Receptors, GABA-A/genetics, Receptors, GABA-A/metabolism, Seizures/genetics, Seizures/metabolism, Seizures/pathology, Seizures/physiopathology, GABAA receptor, Guanidinoacetate, Guanidinoacetate methyltransferase deficiency, Picrotoxin, Seizures
Pubmed
Web of science
Create date
16/02/2016 17:31
Last modification date
20/08/2019 15:28
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