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Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP

Bauchwitz, Dr. Robert (2005) Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. [Journal (Paginated)]

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Abstract

Fragile X Syndrome is the most common form of inherited mental retardation worldwide. A Fragile X mouse model, fmr1, with a disruption in the X-linked Fmr1 gene, has three substantial deficits observed in several strains: (1) sensitivity to audiogenic seizures (AGS), (2) tendency to spend significantly more time in the center of an open field, and (3) enlarged testes. Alterations in metabotropic glutamate receptor group I signaling were previously identified in the fmr1 tm1Cgr mouse. In this study, we examined the effect of MPEP, an antagonist of the group I metabotropic glutamate receptor mGluR5, on audiogenic seizures and open field activity of fmr1 tm1Cgr mice. Genetic analysis revealed synergistic reactions between fmr1tm1Cgr and inbred AGS alleles. In addition, AGS sensitivity due to the fmr1 tm1Cgr allele was restricted during development. Examination of phenotypes combining mGluR5 inhibition and Fmr1 mutation indicated that absence of FMRP may affect mGluR5 signaling through indirect as well as direct pathways. All strains of fmr1 tm1Cgr mice tested (FVB/NJ, C57BL/6J, and an F1 hybrid of the two) had a more excitable AGS pathway than wild-type, and consequently required more MPEP to achieve seizure suppression. At high doses of mGluR5 antagonists, a Fragile X specific tolerance (loss of drug activity) was observed. The tolerance effect could be overcome by a further increase in drug dose. In open field tests, MPEP reduced fmr1 tm1Cgr center field behavior to one indistinguishable from wild-type. Therefore, mGluR5 antagonists were able to rescue two of the major phenotypes of the FX mouse. Modulation of mGluR5 signaling may allow amelioration of symptoms of Fragile X Syndrome.

Item Type:Journal (Paginated)
Additional Information:The supplementary material pdf file found here is presented in its complete form as originally accepted. At some point after acceptance, between 2005 and 2009, the text was lost on the publisher's website. (Note: The publisher's website has been corrected as of June 17, 2009.)
Keywords:Fragile X; mGluR; MPEP; audiogenic seizures; open field; fmr1
Subjects:Neuroscience > Neuropharmacology
ID Code:6538
Deposited By:Bauchwitz, Dr. Robert
Deposited On:10 Jun 2009 09:01
Last Modified:11 Mar 2011 08:57

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