Transgenic Mouse Model Studies of Fragile X Syndrome

With a $410,000 grant from FRAXA Research Foundation from 1999-2001, Dr. Eric Kandel and his team at Columbia University researched development of Fragile X mice to further aid future studies of Fragile X research.

Dr. Eric Kandel, MD, Columbia University, FRAXA research grant
$410,000 Grant
Eric Kandel, MD
Principal Investigator

Sally Till, PhD
FRAXA Postdoctoral Fellow

Dusan Bartsch, PhD
FRAXA Postdoctoral Fellow

Columbia University
1999-2001 FRAXA Research Grant
$410,000 over 3 Years

Temporal and Spatial Restriction of FMR1 Expression in Mouse Forebrain

by Eric Kandel, 6/1/1999

Fragile X syndrome is the most frequent inherited cause of mental retardation. Fragile X pathology is linked to the alterations of the FMR1 gene encoding the FMR1 protein. Our aim is to develop genetically modified mice that would enable us both to explore the role of FMR1 gene and its protein product FMRP in neuronal function and in the cognitive defects of Fragile X syndrome. By this means we have to facilitate the development of therapeutic approaches to Fragile X.

To develop effective approaches to therapy, we need to determine the developmental time window during which the absence of the FMR1 protein damages brain function. Does the damage occur prenatally or postnatally? If Fragile X defects are induced in brain prenatally, during development, can the damage be reversed by reactivating the gene postnatally? What is the optimal and necessary time window for the gene reactivation to restore cognitive function? In which parts of the brain has the FMR1 gene been activated to restore the function? To address these questions, we propose to develop two new types of genetically modified mice:

First, we will develop a mouse with the FMR1 gene specifically ablated (knocked out) in the forebrain using the cre/lox P system. This restriction of the knockout will allow us to study specifically the role of the FMR1 gene and its product FMRP in those brain structures associated with higher cognitive function, without the complicating effects of FMR1 gene knockout in other tissues.

Second, in a complementary approach, we will generate transgenic mice with tetracycline inducible, temporally and spatially regulated FMR1 expressed in the mouse forebrain. We will use these transgenic mice in conjunction with the already existing complete FMR1 knockout mice to study the role of FMR1 protein in the brain areas implica-ted in higher cognitive functions and learning and memory with high temporal and spatial specificity. We plan to use both these mice to evaluate the potentials of demethylation therapy and gene therapy.

Dr. Eric Kandel, MD, Columbia University, FRAXA research grant

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