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Modulation of behavioral phenotypes by a muscarinic M1 antagonist in a mouse model of fragile X syndrome

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Abstract

Rationale

Muscarinic acetylcholine receptors (mAChR) are G protein-coupled receptors, widely expressed in the CNS. Electrophysiological and molecular studies have provided evidence for overactive M1 receptor signaling in the fragile X knockout (Fmr1 KO) mouse model, suggesting the involvement of the M1 receptors in fragile X syndrome. Overactive signaling through the M1 receptor has been hypothesized to contribute to the phenotypes seen in fragile X mice.

Objective

We investigated the modulation of behavioral responses in the Fmr1 KO animals by reducing the activity through the muscarinic M1 receptor using the pharmacological agent dicyclomine, an M1 antagonist.

Methods

The behavioral assays used to investigate the pharmacological effects include marble burying (perseverative behavior), open-field exploration (activity), passive avoidance (learning and memory), prepulse inhibition (sensorimotor gating), and audiogenic seizures.

Results

Data from the marble-burying assay suggests that treatment with dicyclomine results in a decrease in the number of marbles buried in the wild-type and in the KO animals. To examine the possibility of drug-induced sedation, overall activity was measured in an open-field chamber. Dicyclomine only increases activity at a dose of 20 mg/kg in the wild-type mice but did not affect exploration in the KO animals. Lastly, we observed that dicyclomine causes a significant decrease in the percentage of audiogenic seizures in the Fmr1 KO animals.

Conclusion

Our findings suggest that pharmacologically reducing the activity through the mAChR M1 alters select behavioral responses in the Fmr1 KO mice.

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Abbreviations

mAChR:

Muscarinic acetylcholine receptor

WT:

Wild type

KO:

Knockout

MB:

Marble burying

OFA:

Open-field activity

PPI:

Prepulse inhibition

PA:

Passive avoidance

AGS:

Audiogenic seizures

mg:

Milligram

kg:

Kilogram

s:

Second

cm:

Centimeter

dB:

Decibel

ANOVA:

Analysis of variance

SEM:

Standard error of the mean

FXS:

Fragile X syndrome

FMRP:

Fragile X mental retardation protein

mGluR:

Metabotropic glutamate receptors

LTD:

Long-term depression

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Acknowledgments

This research was supported by the Baylor Fragile X Center and the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center. We would like to thank Dr. Corinne Spencer for her valuable suggestions and input into the project.

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

    Surabi Veeraragavan, Nghiem Bui, Jennie R. Perkins, Lisa A. Yuva-Paylor & Richard Paylor

  2. Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA

    Richard Paylor

  3. Seaside Therapeutics, 840 Memorial Drive, Cambridge, MA, 02139, USA

    Randall L. Carpenter

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  1. Surabi Veeraragavan
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  2. Nghiem Bui
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  3. Jennie R. Perkins
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  4. Lisa A. Yuva-Paylor
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  5. Randall L. Carpenter
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  6. Richard Paylor
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Correspondence to Richard Paylor.

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Veeraragavan, S., Bui, N., Perkins, J.R. et al. Modulation of behavioral phenotypes by a muscarinic M1 antagonist in a mouse model of fragile X syndrome. Psychopharmacology 217, 143–151 (2011). https://doi.org/10.1007/s00213-011-2276-6

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  • DOI: https://doi.org/10.1007/s00213-011-2276-6

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