Elsevier

Biological Psychiatry

Volume 75, Issue 3, 1 February 2014, Pages 189-197
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2013.05.038Get rights and content

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.

Section snippets

Mice

Fmr1 KO mice (19) were obtained from Jackson Laboratories(Bar Harbor, Maine) and maintained on a congenic C57BL/6J background. All animal work was approved by local Swiss veterinary authority, and all experiments were conducted with experimenters blind to genotype and drug treatment.

Drugs and Treatment

CTEP, MPEP, and [3H]-ABP688 were synthesized at F. Hoffmann-La Roche AG (Basel, Switzerland) CTEP was formulated as microsuspension in vehicle (.9 % sodium chloride, .3 % Tween-80). Chronic treatment started at the

Correction of Learning Deficit in the Inhibitory Avoidance and Extinction Task

Cognitive deficits are a core symptom of FXS, which is reproduced in Fmr1 KO mice (2). In agreement with previous results 6, 23, 24, Fmr1 KO mice exhibited a robust deficit in the acquisition of the IAE task. The latency to enter the dark compartment was significantly reduced in vehicle-treated Fmr1 KO mice compared with WT littermates 6 hours after conditioning (p = .042; Figure 1C,D). This deficit persisted at the 24-hour test session after one (p = .048) but not two (p = .14) extinction

Discussion

The current study examined for the first time the alterations in brain activity patterns in a vertebrate model of fragile X with and without chronic pharmacologic inhibition of mGlu5, employing fMRI in Fmr1 KO and WT mice. In addition, principal component regression was explored as a means to extract interrelationships between brain activity patterns and learning or extinction capacities. Furthermore, mGlu5 expression levels were quantified across numerous brain areas in both genotypes.

References (59)

  • C. Luscher et al.

    Group 1 mGluR-dependent synaptic long-term depression: Mechanisms and implications for circuitry and disease

    Neuron

    (2010)
  • J.A. Detre et al.

    Perfusion magnetic resonance imaging with continuous arterial spin labeling: Methods and clinical applications in the central nervous system

    Eur J Radiol

    (1999)
  • I. Ehrlich et al.

    Amygdala inhibitory circuits and the control of fear memory

    Neuron

    (2009)
  • K.C. Liang et al.

    Post-training amygdaloid lesions impair retention of an inhibitory avoidance response

    Behav Brain Res

    (1982)
  • M.B. Parent et al.

    Posttraining infusion of lidocaine into the amygdala basolateral complex impairs retention of inhibitory avoidance training

    Brain Res

    (1994)
  • D. Inta et al.

    The mGlu5 receptor antagonist MPEP activates specific stress-related brain regions and lacks neurotoxic effects of the NMDA receptor antagonist MK-801: Significance for the use as anxiolytic/antidepressant drug

    Neuropharmacology

    (2012)
  • E.A. Phelps

    Human emotion and memory: Interactions of the amygdala and hippocampal complex

    Curr Opin Neurobiol

    (2004)
  • D. Hessl et al.

    Cortisol and behavior in fragile X syndrome

    Psychoneuroendocrinology

    (2002)
  • J.C. Lauterborn

    Stress induced changes in cortical and hypothalamic c-fos expression are altered in fragile X mutant mice

    Brain Res Mol Brain Res

    (2004)
  • J.A. Markham et al.

    Corticosterone response to acute stress in a mouse model of Fragile X syndrome

    Psychoneuroendocrinology

    (2006)
  • J. Ellegood et al.

    Anatomical phenotyping in a mouse model of fragile X syndrome with magnetic resonance imaging

    Neuroimage

    (2010)
  • M.R. Vianna et al.

    Memory extinction requires gene expression in rat hippocampus

    Neurobiol Learn Mem

    (2003)
  • J.I. Rossato et al.

    On the participation of hippocampal p38 mitogen-activated protein kinase in extinction and reacquisition of inhibitory avoidance memory

    Neuroscience

    (2006)
  • M.R. Milad et al.

    Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert

    Biol Psychiatry

    (2007)
  • A. Schneider et al.

    Fragile X syndrome -- from genes to cognition

    Dev Disabil Res Rev

    (2009)
  • M. Bernardet et al.

    Fmr1 KO mice as a possible model of autistic features

    Scientific World Journal

    (2006)
  • G. Dölen et al.

    Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome

    J Physiol

    (2008)
  • D. Hessl et al.

    Amygdala dysfunction in men with the fragile X premutation

    Brain

    (2007)
  • K.M. Dalton et al.

    Brain function and gaze fixation during facial-emotion processing in fragile X and autism

    Autism Res

    (2008)
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