Infantile spasms and Down syndrome: a new animal model.
Infantile spasms is a catastrophic childhood seizure disorder for which few animal models exist. Children with Down syndrome are highly susceptible to infantile spasms. The Ts65Dn mouse is a valid model for Down syndrome; therefore, we tested the hypothesis that the Ts65Dn mouse represents a substrate for an animal model of infantile spasms. The baseline of naïve Ts65Dn mice showed spontaneous spike-and-wave discharges, a pattern that worsened with baclofen and gamma-butyrolactone, which induced acute epileptic extensor spasms (AEES) associated with epileptiform polyspike bursts and an electrodecremental response on the EEG. GABABR-agonist-induced AEES were significantly reduced with vigabatrin, rodent ACTH fragment, valproic acid, ethosuximide, and CGP 35348. Porcine ACTH had no effect. GABABR protein expression was significantly increased in the thalamus and medulla oblongata of Ts65D mice in comparison with wild-type controls. The GABABR agonist-treated Ts65Dn mouse shows the unique clinical, electrographic, and pharmacologic signature of infantile spasms and represents a valid, acute model of this disorder. GABABR-mediated mechanisms may contribute to the increased susceptibility of children with Down syndrome to infantile spasms.
Cortez
Miguel A
MA
Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
Shen
Liqing
L
Wu
Ying
Y
Aleem
Ilyas S
IS
Trepanier
Catherine H
CH
Sadeghnia
Hamid R
HR
Ashraf
Asim
A
Kanawaty
Ashlin
A
Liu
Chen-Chu
CC
Stewart
Lee
L
Snead
O Carter
OC
D015107:4-Butyrolactone; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001418:Baclofen; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D004569:Electroencephalography; D005013:Ethosuximide / Q000494:pharmacology; D018755:GABA Agonists; D005838:Genotype; D006801:Humans; D007223:Infant; D051379:Mice; D008817:Mice, Mutant Strains; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010641:Phenotype; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D018080:Receptors, GABA-B / Q000187:drug effects / Q000378:metabolism*; D013036:Spasms, Infantile / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology; D020888:Vigabatrin / Q000494:pharmacology
D000927:Anticonvulsants; D018755:GABA Agonists; D009943:Organophosphorus Compounds; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D005013:Ethosuximide; D014635:Valproic Acid; C066430:CGP 35348; D020888:Vigabatrin; D001418:Baclofen; D015107:4-Butyrolactone