Impaired conditioned fear and enhanced long-term potentiation in Fmr2 knock-out mice.
FRAXE mental retardation results from expansion and methylation of a CCG trinucleotide repeat located in exon 1 of the X-linked FMR2 gene, which results in transcriptional silencing. The product of FMR2 is a member of a family of proteins rich in serine and proline, members of which have been associated with transcriptional activation. We have developed a murine Fmr2 gene knock-out model by replacing a fragment containing parts of exon 1 and intron 1 with the Escherichia coli lacZ gene, placing lacZ under control of the Fmr2 promoter. Expression of lacZ in the knock-out animals indicates that Fmr2 is expressed in several tissues, including brain, bone, cartilage, hair follicles, lung, tongue, tendons, salivary glands, and major blood vessels. In the CNS, Fmr2 expression begins at the time that cells in the neuroepithelium differentiate into neuroblasts. Mice lacking Fmr2 showed a delay-dependent conditioned fear impairment. Long-term potentiation (LTP) was found to be enhanced in hippocampal slices of Fmr2 knock-out compared with wild-type littermates. To our knowledge, this mouse knock-out is the first example of an animal model of human mental retardation with impaired learning and memory performance and increased LTP. Thus, although a number of studies have suggested that diminished LTP is associated with memory impairment, our data suggest that increased LTP may be a mechanism that leads to impaired cognitive processing as well.
Gu
Yanghong
Y
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
McIlwain
Kellie L
KL
Weeber
Edwin J
EJ
Yamagata
Takanori
T
Xu
Bisong
B
Antalffy
Barbara A
BA
Reyes
Christine
C
Yuva-Paylor
Lisa
L
Armstrong
Dawna
D
Zoghbi
Huda
H
Sweatt
J David
JD
Paylor
Richard
R
Nelson
David L
DL
D000818:Animals; D001522:Behavior, Animal; D015139:Blotting, Southern; D002678:Chimera; D002874:Chromosome Mapping; D003214:Conditioning, Classical; D004195:Disease Models, Animal; D005239:Fear / Q000502:physiology; D005600:Fragile X Syndrome / Q000150:complications / Q000503:physiopathology*; D015870:Gene Expression; D018390:Gene Targeting; D066298:In Vitro Techniques; D008607:Intellectual Disability / Q000209:etiology / Q000503:physiopathology; D007859:Learning Disabilities / Q000209:etiology / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000235:genetics; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D009928:Organ Specificity; D010641:Phenotype; D011401:Promoter Regions, Genetic; D015996:Survival Rate; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics
C512744:Aff2 protein, mouse; D009687:Nuclear Proteins; D015534:Trans-Activators