With a $229,000 grant from FRAXA Research Foundation in 2006, Drs. Richard Paylor, David Albeck, and Francis Brennan at the Baylor College of Medicine compared knockout mice, which lack FMRP, with YAC mice, which express excessive levels of FMRP. Interestingly, knockout mice showed hyperactivity and low anxiety, whereas YAC mice demonstrated high anxiety and low activity.
Kellie Lugenbeal, PhD
FRAXA Postdoctoral Fellow (2000)
The team aimed to better understand the nature of the anxiety-related responses in knockout and YAC mice by evaluating them on multiple types of anxiety tests. They applied pharmacological interventions in the mice 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 determined 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.
by Richard Paylor, 2/1/2005
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 discovered that FMR1 knockout mice have a profound impairment on a specific test of learning: 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.