Infantile Spasms and Down Syndrome: A New Animal Model

Abstract

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 ␥-butyrolactone, which induced acute epileptic extensor spasms (AEES) associated with epileptiform polyspike bursts and an electrodecremental response on the EEG. GABA B R-agonist-induced AEES were significantly reduced with vigabatrin, rodent ACTH fragment, valproic acid, ethosuximide, and CGP 35348. Porcine ACTH had no effect. GABA B R protein expression was significantly increased in the thalamus and medulla oblongata of Ts65D mice in comparison with wild-type controls. The GABA B R agonist-treated Ts65Dn mouse shows the unique clinical, electrographic, and pharmacologic signature of infantile spasms and represents a valid, acute model of this disorder. GABA B R-mediated mechanisms may contribute to the increased susceptibility of children with Down syndrome to infantile spasms. (Pediatr Res 65: 499-503, 2009)

Novel Animal Models of Pediatric Epilepsy

“…The spike-wave discharges are similar to those induced in normal rats exposed to GABA B receptor agonists [59]. It has also been shown that the Ts65Dn mice overexpress GABA B receptors, which prompted the suggestion that the use of GABA B receptor agonists might increase seizure susceptibility [58]. The administration of baclofen or γ-butyrolactone (the pro-drug of the GABA B agonist γ-hydroxybutyrate) to Ts65Dn mice (1 week to 2 months old) results in clusters of extensor spasms with polyspikewave bursts and electrodecrement on EEG recording, whereas γ-butyrolactone injected into wild-type mice causes spike-wave discharges and absence seizures [59].…”

“…Ts65Dn mice exhibit spontaneous spike-wave discharges in EEG recordings without any seizures at baseline [58]. The spike-wave discharges are similar to those induced in normal rats exposed to GABA B receptor agonists [59].…”

“…The administration of baclofen or γ-butyrolactone (the pro-drug of the GABA B agonist γ-hydroxybutyrate) to Ts65Dn mice (1 week to 2 months old) results in clusters of extensor spasms with polyspikewave bursts and electrodecrement on EEG recording, whereas γ-butyrolactone injected into wild-type mice causes spike-wave discharges and absence seizures [59]. antiepileptic drugs used to treat infantile spasms (ACTH and vigabatrin) improve these epileptic phenomenon, suggesting this model of spasms is pharmacologically reliable [58,60]. Assessment of the long-term consequences would be interesting.…”

Getting rid of the catastrophe: frontier research in infantile spasms

“…Higher expression of GABA B receptors in specific brain sites including the thalamus Tomonori Ono, et al and the medulla oblongata together with GABA B -mediated effects may be the fundamental mechanism of spasmsogenesis in this model. Moreover, pretreatment with rodent ACTH 1-24 fragment, vigabatrin, valproic acid, and ethosuximide suppresses chemicallyinduced flexion spasms [25]. In contrast, spasms in this model are not affected by porcine ACTH 1-39 .…”

“…Another model of chemically-induced spasms is produced in a mouse genetic model of Down syndrome (Ts65Dn) [25]. IS occur in approximately 10% of patients with Down syndrome [26].…”