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Chronic Metabotropic Glutamate Receptor 5 Inhibition Corrects Local Alterations of Brain Activity and Improves Cognitive Performance in Fragile X Mice

      Background

      Fragile X syndrome (FXS) is the most common genetic cause for intellectual disability. Fmr1 knockout (KO) mice are an established model of FXS. Chronic pharmacological inhibition of metabotropic glutamate receptor 5 (mGlu5) in these mice corrects multiple molecular, physiological, and behavioral phenotypes related to patients’ symptoms. To better understand the pathophysiology of FXS and the effect of treatment, brain activity was analyzed using functional magnetic resonance imaging in relation to learning and memory performance.

      Methods

      Wild-type (WT) and Fmr1 KO animals receiving chronic treatment with the mGlu5 inhibitor CTEP or vehicle were evaluated consecutively for 1) learning and memory performance in the inhibitory avoidance and extinction test, and 2) for the levels of brain activity using continuous arterial spin labeling based functional magnetic resonance imaging. Neural activity patterns were correlated with cognitive performance using a multivariate regression analysis. Furthermore, mGlu5 receptor expression in brains of untreated mice was analyzed by autoradiography and saturation analysis using [3H]-ABP688.

      Results

      Chronic CTEP treatment corrected the learning deficit observed in Fmr1 KO mice in the inhibitory avoidance and extinction test and prevented memory extinction in WT and Fmr1 KO animals. Chronic CTEP treatment normalized perfusion in the amygdala and the lateral hypothalamus in Fmr1 KO mice and furthermore decreased perfusion in the hippocampus and increased perfusion in primary sensorimotor cortical areas. No significant differences in mGlu5 receptor expression levels between Fmr1 WT and KO mice were detected.

      Conclusions

      Chronic mGlu5 inhibition corrected the learning deficits and partially normalized the altered brain activity pattern in Fmr1 KO mice.

      Key Words

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      Linked Article

      • Portraying Inhibition of Metabotropic Glutamate Receptor 5 in Fragile X Mice
        Biological PsychiatryVol. 75Issue 3
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          The human genome project and genetic mapping of various common disorders have been considered to have opened a new area in our understanding of the pathophysiology of human illnesses and their treatment. However, the polygenic nature of the vast majority of diseases, interactions between multiple genes and genetic modifiers, as well as epigenetic factors represent a high level of complexity that has turned out to be a real barrier for developing effective therapies on the basis of genetic observations.
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