title: Chronic metabotropic glutamate receptor 5 inhibition corrects local alterations of brain activity and improves cognitive performance in fragile X mice.
abstract: 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 [(3)H]-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.
authors.affiliation: Discovery Neuroscience, F. Hoffmann-La Roche AG, Pharma Research & Early Development, Basel.
authors.forename: Aubin
authors.initials: A
authors.lastname: Michalon
authors.affiliation: Discovery Neuroscience, F. Hoffmann-La Roche AG, Pharma Research & Early Development, Basel.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bruns
authors.affiliation: Discovery Neuroscience, F. Hoffmann-La Roche AG, Pharma Research & Early Development, Basel.
authors.forename: Céline
authors.initials: C
authors.lastname: Risterucci
authors.affiliation: Discovery Neuroscience, F. Hoffmann-La Roche AG, Pharma Research & Early Development, Basel.
authors.forename: Michael
authors.initials: M
authors.lastname: Honer
authors.affiliation: Discovery Neuroscience, F. Hoffmann-La Roche AG, Pharma Research & Early Development, Basel.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Ballard
authors.affiliation: Discovery Neuroscience, F. Hoffmann-La Roche AG, Pharma Research & Early Development, Basel.
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.affiliation: Discovery Chemistry, F. Hoffmann-La Roche AG, Pharma Research & Early Development, Basel; and Neurimmune Holding AG, Schlieren, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Jaeschke
authors.affiliation: Discovery Neuroscience, F. Hoffmann-La Roche AG, Pharma Research & Early Development, Basel.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Wettstein
authors.affiliation: Discovery Neuroscience, F. Hoffmann-La Roche AG, Pharma Research & Early Development, Basel.
authors.forename: Markus
authors.initials: M
authors.lastname: von Kienlin
authors.affiliation: Discovery Neuroscience, F. Hoffmann-La Roche AG, Pharma Research & Early Development, Basel.
authors.forename: Basil
authors.initials: B
authors.lastname: Künnecke
authors.affiliation: Discovery Neuroscience, F. Hoffmann-La Roche AG, Pharma Research & Early Development, Basel. Electronic address: lothar.lindemann@roche.com.
authors.forename: Lothar
authors.initials: L
authors.lastname: Lindemann
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004597:Electroshock / Q000009:adverse effects; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005108:Extinction, Psychological / Q000187:drug effects; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007093:Imidazoles / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D010091:Oximes / Q000493:pharmacokinetics; D010100:Oxygen / Q000097:blood; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D007093:Imidazoles; D010091:Oximes; D010100:Oxygen; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D014316:Tritium; C569289:2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine; C510950:3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime; C497684:Fmr1 protein, mouse; C121465:6-methyl-2-(phenylethynyl)pyridine
keywords: Amygdala; CTEP; Fmr1 KO mice; fMRI; fragile x syndrome (FXS); mGlu5 receptor