title: Genetic reduction of muscarinic M4 receptor modulates analgesic response and acoustic startle response in a mouse model of fragile X syndrome (FXS).
abstract: BACKGROUND
  The G-protein coupled muscarinic acetylcholine receptors, widely expressed in the CNS, have been implicated in fragile X syndrome (FXS). Recent studies have reported an overactive signaling through the muscarinic receptors in the Fmr1KO mouse model. Hence, it was hypothesized that reducing muscarinic signaling might modulate behavioral phenotypes in the Fmr1KO mice. Pharmacological studies from our lab have provided evidence for this hypothesis, with subtype-preferring muscarinic M1 and M4 receptor antagonists modulating select behaviors in the Fmr1KO mice. Since the pharmacological antagonists were not highly specific, we investigated the specific role of M4 receptors in the Fmr1KO mouse model, using a genetic approach.
  
  
  METHODS
  We created a double mutant heterozygous for the M4 receptor gene and hemizygous for the Fmr1 gene and examined the mutants on various behaviors. Each animal was tested on a behavior battery comprising of open-field activity (activity), light-dark (anxiety), marble burying (perseverative behavior), prepulse inhibition (sensorimotor gating), rotarod (motor coordination), passive avoidance (learning and memory) and hotplate (analgesia). Animals were also tested on the audiogenic seizure protocol and testis weights were measured.
  
  
  RESULTS
  Reduction of M4 receptor expression in the heterozygotes completely rescued the analgesic response and partly rescued the acoustic startle response phenotype in the Fmr1KO mice. However, no modulation was observed in a number of behaviors including learning and memory, activity, perseverative behavior and audiogenic seizures.
  
  
  CONCLUSIONS
  Reducing M4 receptor signaling altered only select behavioral phenotypes in the Fmr1KO mouse model, suggesting that other targets are involved in the modulation of fragile X behaviors.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. veerarag@bcm.edu
authors: Surabi
authors: S
authors: Veeraragavan
authors: Deanna
authors: D
authors: Graham
authors: Nghiem
authors: N
authors: Bui
authors: Lisa A
authors: LA
authors: Yuva-Paylor
authors: Jürgen
authors: J
authors: Wess
authors: Richard
authors: R
authors: Paylor
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009929:Organ Size; D010147:Pain Measurement / Q000379:methods; D043588:Receptor, Muscarinic M4 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013216:Reflex, Startle / Q000235:genetics / Q000502:physiology*; D013737:Testis / Q000473:pathology
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D043588:Receptor, Muscarinic M4; C497684:Fmr1 protein, mouse