Abstract
Rationale
Abnormal dendritic spine morphology is a significant neuroanatomical defect in fragile X mental retardation. It has been suggested that overactive group 1 metabotropic glutamate receptor (mGlu) signaling is associated with the spine dysmorphology occurring in fragile X syndrome (FXS). Thus, group 1 mGlu became a new therapeutic target for the treatment of FXS.
Objective
The purpose of this study was to identify the effect of inhibition of mGlu signaling in FXS.
Methods
We observed the changes in dendritic spines after pharmacological modulation of mGlu signaling in an Fmr1 knockout (KO) mouse model.
Results
The activation of group 1 mGlu resulted in elongation of dendritic spines in the cultured neurons derived from Fmr1 KO mice and wild-type (WT) mice. Antagonism of group 1 mGlu reduced the average spine length of Fmr1 KO neurons. Furthermore, systemic administration of the selective group 1 mGlu5 antagonist 2-methyl-6-phenylethynyl pyridine (MPEP) reduced the average spine length and density in the cortical neurons of Fmr1 KO mice at developmental age. For the adult mice, MPEP administration was less effective for the restoration of spine length. The percentage of immature spines showed a similar reduction in parallel to the changes of spine length. Temporary MPEP intervention with single-dose treatment did not show any effect.
Conclusion
These results show that MPEP administration could partially rescue the morphological deficits of dendritic spines in Fmr1 KO mice at developmental age.
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Abbreviations
- mGlu:
-
Metabotropic glutamate receptor
- FXS:
-
Fragile X syndrome
- KO:
-
Knockout
- WT:
-
Wild type
- MPEP:
-
2-Methyl-6-phenylethynyl pyridine
- FMRP:
-
Fragile X mental retardation protein
- DHPG:
-
(S)-3,5-Dihydroxyphenylglycine
- PHCCC:
-
N-Phenyl-7-(hydroxyimino) cyclopropa-[b]chromen-1a-carboxamide
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Acknowledgement
This research was supported by the National Nature Science Foundation of China (grant number 30870876) and the Natural Science Foundation of Guangdong Province of China (grant number 2008B030301250).
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Tau Su and Hong-Xing Fan contributed equally to this work
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Su, T., Fan, HX., Jiang, T. et al. Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome. Psychopharmacology 215, 291–300 (2011). https://doi.org/10.1007/s00213-010-2130-2
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DOI: https://doi.org/10.1007/s00213-010-2130-2