期刊
BEHAVIOURAL BRAIN RESEARCH
卷 228, 期 1, 页码 1-8出版社
ELSEVIER
DOI: 10.1016/j.bbr.2011.11.018
关键词
Fragile X syndrome; Muscarinic; M-4 receptors; Analgesic response; Behavior; Sensorimotor gating
资金
- Baylor Fragile X Center
- Baylor College of Medicine Intellectual and Developmental Disabilities Research Center
Introduction: 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 M-1 and M-4 receptor antagonists modulating select behaviors in the Fmr1KO mice. Since the pharmacological antagonists were not highly specific, we investigated the specific role of M-4 receptors in the Fmr1KO mouse model, using a genetic approach. Methods: We created a double mutant heterozygous for the M-4 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 M-4 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. Conclusion: Reducing M-4 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. (C) 2011 Elsevier B.V. All rights reserved.
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