To understand the role of the FMR1 gene and its product FMRP in central nervous system function, researchers have engineered a mouse that lacks FMRP (the FMR1 knockout mouse). Although several laboratories have found that these mice are hyperactive, have abnormal startle responses, and are prone to seizures, there appears to be no consistent learning and memory impairment in the mice. This has hampered efforts to identify and test therapeutic interventions for the cognitive impairments associated with Fragile X.

We have recently discovered that FMR1 knockout mice have a profound impairment on a specific test oflearning: the lever press escape/avoidance test. Performance in this test can be associated with changes in two neuropeptides: brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in various brain regions.

Our project has three goals:

1.To better understand this learning impairment

2. To determine whether there is a relationship between BDNF and NGF levels and the avoidance learning of FMR1 KO mice.

3.To rescue the leverpress avoidance learning impairment with MPEP and/or ampakines, while monitoring changes in BDNF and NGF levels. With this robust learning impairment in mice, we believe we are in a unique position to better understand the role of FMRP in learning and memory and to evaluate potential treatments.

Richard Paylor, Ph.D., Principal Investigator
Kellie Lugenbeal, Ph.D., Postdoctoral Fellow
Baylor College of Medicine
$109,000 awarded January 2000

by Katie Clapp, 3/2000

Preliminary studies by this team indicate that, in mice as in humans, the level of fragile X protein in brain cells plays a prominent role in determining levels of activity and anxiety. Dr. Paylor's group is comparing knockout mice, which lack FMRP, with YAC mice, which express excessive levels of FMRP. Interestingly, knockout mice show hyperactivity and low anxiety, whereas YAC mice demonstrate high anxiety and low activity. The team aims to better understand the nature of the anxiety-related responses in knockout and YAC mice by evaluating them on multiple types of anxiety tests. Then, they will apply pharmacological interventions in these mice, to begin to evaluate the role of different neurotransmitter systems in regulating the abnormal anxiety-related responses. By evaluating the effects of particular drugs on anxiety and activity in the knockout and YAC mice, they will determine whether the mice will be a useful tool for screening new drugs in the future, for potential use in treating patients with fragile X syndrome.