Audiogenic Seizures Susceptibility in Transgenic Mice with Fragile X Syndrome

Abstract

Summary:Purpose: To evaluate their susceptibility to audiogenic seizures, five groups of knockout mice with various forms of fragile X genetic involvement [hemizygous males (n = 46), and homozygous (n = 38) and heterozygous females (n = 45), and their normal male (n = 45) and female (n = 52) littermates] were studied.Methods: All mouse groups were tested at ages 17, 22, 35, and 45 days. Audiogenic seizure susceptibility was scored, and the analysis of variance was used for the evaluation of the effects of age and genetic condition on seizure severity score (SSS).Results: All groups of knockout fragile X mice exhibited SSSs significantly higher than those observed in their wild-type littermates; among knockout mice, hemizygous males and homozygous females showed the highest SSSs. Hemizygous males showed higher SSSs with increasing age, from 17 to 45 days; homozygous females showed a peak at age 22 days, followed by a decrease; finally, heterozygous females had their highest SSSs at age 17 days.Conclusions: This study demonstrates that an increased susceptibility to audiogenic seizures is present in fragile X knockout mice at all the ages tested. These results support the validity of this animal model also for epilepsy and seizures in the human fragile X syndrome.

Wild-Type Male Offspring of fmr-1+/− Mothers Exhibit Characteristics of the Fragile X Phenotype

“…Importantly, both H and KO females exhibit hyperactivity (Musumeci et al, 2000;Qin et al, 2005) suggesting that this behavior may be transmitted epigenetically from mother to offspring. Since the D2 receptor is fundamentally important in regulating the DA system and behavioral activity, and because the response of hyperactive offspring to a D2 agonist is reduced, the receptor or its coupling/signalling is a candidate target for the maternal effect.…”

Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice

“…Therefore, eyelid startle measurement allows for a better dissection of the more subtle differences in startle behavior. In addition, our method allows us to reduce the sound pressure levels necessary for startle induction which is relevant since Fmr1 KO mice react strongly to loud acoustic stimuli and are highly susceptible to audiogenic seizures (Musumeci et al, 2000). In another study, PPI in Fmr1 KO mice was not significantly altered (Spencer et al, 2006).…”

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

“…However, as opposed to the spontaneous seizures observed in FXS patients, seizures in Fmr1 knockout mice are specifically triggered by auditory stimuli (Musumeci et al, 2000;Chen and Toth, 2001). Seizure incidence in knockout mice have been shown peak in the third week of postnatal life (Yan et al, 2005).…”

“…Fmr1 knockout mice are susceptible to audiogenic seizures (Musumeci et al, 2000;Dolen et al, 2007;Musumeci et al, 2007). We tested the anticonvulsant effects of drugs that potentiate GABA A receptor activity in Fmr1 knockout mice.…”