title: Systemic availability of guanidinoacetate affects GABAA receptor function and seizure threshold in GAMT deficient mice.
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.
authors.affiliation: Program of Genetics and Genome Biology, Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. andreas.schulze@sickkids.ca.|Department of Pediatrics, University of Toronto, Toronto, ON, Canada. andreas.schulze@sickkids.ca.
authors.forename: A
authors.identifier: 0000-0001-8491-1095
authors.initials: A
authors.lastname: Schulze
authors.affiliation: Program of Genetics and Genome Biology, Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.|Center for Molecular Diseases, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Tran
authors.affiliation: Program of Genetics and Genome Biology, Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Levandovskiy
authors.affiliation: Program of Genetics and Genome Biology, Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Patel
authors.affiliation: Department of Pediatrics, University of Toronto, Toronto, ON, Canada.|Program of Brain and Behavior Neuroscience and Mental Health, Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: Cortez
mesh_terms: D000818:Animals; D000069280:Electrocorticography; D005998:Glycine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D050937:Guanidinoacetate N-Methyltransferase / Q000172:deficiency* / Q000378:metabolism; D007805:Language Development Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009069:Movement Disorders / Q000151:congenital* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D011963:Receptors, GABA-A; D050937:Guanidinoacetate N-Methyltransferase; C004946:glycocyamine; D005998:Glycine
keywords: GABAA receptor; Guanidinoacetate; Guanidinoacetate methyltransferase deficiency; Picrotoxin; Seizures