Developmentally related increased seizure susceptibility to pentylenetetrazole in fragile X knockout mice

Fragile X syndrome is the leading genetic cause of mental retardation. It is caused by over 50 CGG repeats in the X chromosome. The anatomical and behavioral consequences of this mutation are incompletely understood, although several anatomical and behavioral abnormalities have been reported. Additional studies need to be performed to characterize this disease to suggest possible treatments for fragile X syndrome.;There is a relationship between Fragile X Mental Retardation Protein (FMRP) and seizures. Seizures are the second most common neurological disorder and are caused by increased excitation or decreased inhibition. Over 500 genes have been implicated in seizures, including one gene (fmr1) involved in fragile X syndrome. 18--25% of fragile X patients have epilepsy. Fragile X knock out mice have been reported to have increased susceptibility to audiogenic seizures. However, this same study reported no difference between control and knockout mice regarding seizure susceptibility to the chemoconvulsant pentylenetetrazole (PTZ), an antagonist of inhibitory GABA receptors.;The finding that fragile X knockout mice would not be more susceptible to PTZ was both surprising and counterintuitive. I thus performed a similar experiment under more rigorous conditions. I administered 30mg/kg of PTZ to adult control and fragile X knockout mice and recorded the behavioral responses. I noted the times spent in non-seizure activity, myoclonic jerks, and generalized convulsions. I calculated the latency, duration, and number of each of these three observed phases. Our results indicated that fragile X knockout mice had an increased seizure susceptibility as shown by increased duration of myoclonic jerks and total seizure time, as well as number of non-seizure episodes and myoclonic jerks. These findings suggest that fragile X is more seizure susceptible to generalized chemoconvulsants, in addition to the previously reported audiogenic seizure susceptibility.;Because both seizures and fragile X syndrome are developmentally related, I examined PTZ induced seizure susceptibility to juvenile control and fragile X knockout mice. I was expecting both the juvenile control and knockout mice to have greater seizure susceptibility compared to the adult mice of the same experimental condition.;However, both the juvenile control and knockout mice had similar susceptibilities as the adult control mice. Additionally, there was no statistically significant difference between juvenile knockout mice compared to the age-matched controls. This suggests that, similar to audiogenic seizures, the difference in seizure susceptibility to PTZ develops after P10.;These experiments have demonstrated that fragile X knockout mice are more susceptible than control animals to the chemoconvulsant PTZ as adults, but not as juveniles. Furthermore, the temporal progression suggests that there is a developmental involvement in this seizure susceptibility. The mechanism of the seizure susceptibility and temporal progression are areas for further study. With a greater understanding of this general hyperexcitability, more effective treatments for fragile X patients can be devised.