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Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant

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Abstract

Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and autism. The disease is a result of lack of expression of the fragile X mental retardation protein. Brain tissues of patients with FXS and mice with FMRP deficiency have shown an abnormal dendritic spine phenotype. We investigated the dendritic spine length and density of hippocampal CA1 pyramidal neurons in 2-, 10-, and 25-week-old Fmr1 knockout (KO). Next, we studied the effects of long-term treatment with an mGluR5 antagonist, AFQ056/Mavoglurant, on the spine phenotype in adult Fmr1 KO mice. We observed alterations in the spine phenotype during development, with a decreased spine length in 2-week-old Fmr1 KO mice compared with age-match wild-type littermates, but with increased spine length in Fmr1 KO mice compared with 10- and 25-week-old wild-type controls. No difference was found in spine density at any age. We report a rescue of the abnormal spine length in adult Fmr1 KO mice after a long-term treatment with AFQ056/Mavoglurant. This finding suggests that long-term treatment at later stage is sufficient to reverse the structural spine abnormalities and represents a starting point for future studies aimed at improving treatments for FXS.

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Abbreviations

mGluR:

Metabotropic glutamate receptor

FXS:

Fragile X syndrome

KO:

Knockout

WT:

Wild type

PBS:

Phosphate-buffered saline

PFA:

Paraformaldehyde

FMRP:

Fragile X mental retardation protein

FMR1 :

Fragile X mental retardation gene

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Acknowledgments

This work was supported by a grant from the Netherlands Organisation for Health Research and Development (ZonMw, no. 912-07-022) (RW) and from the E-Rare program entitled “Cure FXS” (no. EU/FIS PS09102673) (RW).

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Authors and Affiliations

  1. CBG-Department of Clinical Genetics, Erasmus Medical Centre, Dr. Molewaterplein 55, 3015GE, Rotterdam, The Netherlands

    Andreea S. Pop, Celine E. F. de Esch, Ronald A. M. Buijsen, Ingeborg M. Nieuwenhuizen, Tracy Li, Ben A. Oostra & Rob Willemsen

  2. Smilow Neuroscience Program, New York University School of Medicine, 522 1st Ave, Smilow Research Bldg 608, New York, NY, 10016, USA

    Josien Levenga

  3. Unit of Genetic Epidemiology, Department of Epidemiology, Erasmus Medical Centre, Dr. Molewaterplein 55, 3015GE, Rotterdam, The Netherlands

    Aaron Isaacs

  4. Neuroscience Discovery Group, Novartis Institutes for Biomedical Research, 4002, Basel, Switzerland

    Fabrizio Gasparini

  5. Department of Clinical Genetics, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands

    Rob Willemsen

Authors
  1. Andreea S. Pop
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  2. Josien Levenga
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  3. Celine E. F. de Esch
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  4. Ronald A. M. Buijsen
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  5. Ingeborg M. Nieuwenhuizen
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  6. Tracy Li
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  7. Aaron Isaacs
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  8. Fabrizio Gasparini
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  9. Ben A. Oostra
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  10. Rob Willemsen
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Correspondence to Rob Willemsen.

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Pop, A.S., Levenga, J., de Esch, C.E.F. et al. Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant. Psychopharmacology 231, 1227–1235 (2014). https://doi.org/10.1007/s00213-012-2947-y

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  • DOI: https://doi.org/10.1007/s00213-012-2947-y

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