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Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome

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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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Authors and Affiliations

  1. Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Chang-gang-dong Road 250, Guangzhou, 510260, China

    Tao Su, Hong-Xing Fan, Tao Jiang, Wei-Wen Sun, Wei-Yi Den, Mei-Mei Gao, Sheng-Qiang Chen, Qi-Hua Zhao & Yong-Hong Yi

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  1. Tao Su
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  2. Hong-Xing Fan
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  3. Tao Jiang
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Correspondence to Yong-Hong Yi.

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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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