Chronic Pharmacological mGlu5 Inhibition Corrects Fragile X in Adult Mice

Neuron. 2012 Apr 12;74(1):49-56. doi: 10.1016/j.neuron.2012.03.009.

Abstract

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, but a crucial unanswered question is whether pharmacological mGlu5 inhibition is able to reverse an already established FXS phenotype in mammals. Here we have used the novel, potent, and selective mGlu5 inhibitor CTEP to address this issue in the Fmr1 knockout mouse. Acute CTEP treatment corrects elevated hippocampal long-term depression, protein synthesis, and audiogenic seizures. Chronic treatment that inhibits mGlu5 within a receptor occupancy range of 81% ± 4% rescues cognitive deficits, auditory hypersensitivity, aberrant dendritic spine density, overactive ERK and mTOR signaling, and partially corrects macroorchidism. This study shows that a comprehensive phenotype correction in FXS is possible with pharmacological intervention starting in young adulthood, after development of the phenotype. It is of great interest how these findings may translate into ongoing clinical research testing mGlu5 inhibitors in FXS patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Disease Models, Animal
  • Drug Administration Schedule
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Imidazoles / therapeutic use*
  • Male
  • Mice
  • Mice, Knockout
  • Phenotype
  • Pyridines / therapeutic use*
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / drug effects*
  • Receptors, Metabotropic Glutamate / metabolism

Substances

  • 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine
  • Excitatory Amino Acid Antagonists
  • Fmr1 protein, mouse
  • Imidazoles
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Fragile X Mental Retardation Protein