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-Gamttm1Isb 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 GamtMUT and GamtWT 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 GamtMUT 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 GamtMUT ECoG phenotype. GamtWT on PTX exhibited electro-behavioral seizures, whereas the GamtMUT did not have PTX induced seizures at the same PTX dose. GamtMUT treated with both ornithine and PTX did not show electro-behavioral seizures while ornithine elevated the PTX seizure threshold of GamtMUT 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.
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Abbreviations
- AGAT:
-
Arginineglycine amidinotransferase
- ECoG:
-
Electrocorticogram
- GAA:
-
Guanidinoacetic acid
- GABA:
-
Gama-amino butyric acid
- GAMT:
-
Guanidinoacetate methyltransferase
- GamtMUT :
-
B6J.Cg-Gamttm1Isb mutant mice
- GamtWT :
-
B6J.Cg-Gamttm1Isb wild type mice
- MUT:
-
Mutant
- ORN:
-
Ornithine
- PTX:
-
Picrotoxin
- SAH:
-
S-adenosyl-l-homocysteine
- SAM:
-
S-adenosyl-l-methionine
- WT:
-
Wild type
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Acknowledgments
The B6J.Cg-Gamttm1Isb transgenic mouse strain was generated and kindly provided by Dr. D. Isbrandt, University Medical Center Hamburg/Eppendorf, Germany.
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All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of and approved by the institution’s animal care committee.
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Schulze, A., Tran, C., Levandovskiy, V. et al. Systemic availability of guanidinoacetate affects GABAA receptor function and seizure threshold in GAMT deficient mice. Amino Acids 48, 2041–2047 (2016). https://doi.org/10.1007/s00726-016-2197-0
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DOI: https://doi.org/10.1007/s00726-016-2197-0