|The Molecular Basis of Increased Seizure Severity in the Fragile X Knockout Mouse
by Carl Dobkin, 1/1/2002
Like many people with Fragile X, the Fragile X knockout mouse is prone to seizures. The mouse is very susceptible to seizures induced by sound (Musumeci et al., 2000). We have found that the Fragile X mouse is also susceptible to seizures induced by the drug kainic acid. However, introduction of a normal human Fragile X gene (FMR1) into this mouse (engineered by Dr. Robert Bauchwitz during a 1998 FRAXA-supported collaboration) eliminates this increased seizure susceptibility.
The heightened seizure susceptibility of the Fragile X mouse implies that there is either an increased function of the excitatory system or decreased function of the inhibitory system in its brain. We aim to find out which one is true. The brain's major inhibitory system is the GABAergic system, named for its dependence on the neurotransmitter GABA, which signals brain neurons to reduce their excitability. We have found a decrease in GABA receptors in the Fragile X mouse brain. We also see an increase in the enzyme that synthesizes GABA, which may be a response to compensate for the reduction in receptors. Preliminary electrophysiological analysis of the Fragile X mouse brain shows functional changes in the GABAergic system. We aim to identify the changes in this system and see which changes are reversed by introducing the human FMR1 gene. Once we determine the critical changes and the cells in which they occur, we will examine how the Fragile X protein influences gene expression in those cells. Since GABA receptors in one brain region, the cerebellum, appear to be unaffected, we will also determine how the GABA system in the cerebellum differs from other brain regions. These strategies should allow us to begin to understand how absence of the Fragile X protein leads to seizures in the Fragile X mouse as well as changes in overall brain function.