|Prepulse inhibition of acoustic startle in Fragile X mice and children
by Paul Frankland, 8/1/2001
Fragile X syndrome is associated with mild to severe learning disabilities, as well as attentional problems. In 1991, scientists discovered the gene (called FMR1) that causes Fragile X. In people with Fragile X, a defect in the FMR1 shuts the gene down. Like a defective factory, the FMR1 gene cannot manufacture the protein it normally makes. The gene is on strike!
The discovery of the Fragile X gene lead to the development of the first Fragile X mouse model. This mutant mouse has been engineered to lack the FMR1 gene, and so, just as in people with Fragile X, no Fragile X protein is manufactured. Because the Fragile X mouse has been found to have learning difficulties, it provides a perfect test ground for potential treatments.
In addition to learning difficulties, individuals with Fragile X typically suffer from deficits in attention and hyperactivity. One way to assess attentional processing in both mice and people is to examine prepulse inhibition of startle. Startle is a fast motor response to a loud noise. If the loud noise is preceded by a much quieter noise, or "prepulse", then the startle response is normally inhibited (or reduced); a process known as "prepulse inhibition". It is thought that disturbances in prepulse inhibition reflect disturbances in attentional processing. Indeed, prepulse inhibition is reduced in a number of cognitive disorders such as schizophrenia and obsessive-compulsive disorder.
We found that prepulse inhibition was dramatically increased in the Fragile X mice. This has opened up the possibility that we can model the attentional deficits observed in Fragile X individuals, by examining prepulse inhibition in Fragile X mice. This way potential therapeutic strategies, aimed at alleviating the behavioral symptoms of Fragile X, can be evaluated in mice. To validate our mouse model, we are currently testing whether children with Fragile X also exhibit disturbances in prepulse inhibition of startle. These studies are being carried out at the UCLA Medical Center, in collaboration with Drs. Ornitz and Dykens.