Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome
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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Preclinical studies have primarily focused on mGluR5 signaling as potential targets for treatment in adult mice.
“Preclinical studies have primarily focused on mGluR5 signaling as potential targets for treatment in adult mice 99,110-113 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [112]
Treatment of Fmr1 knockout mice with the mGluR antagonist MPEP suppressed the audiogenic seizure phenotype and rescued dendritic spine morphology.
“Treatment of Fmr1 KO mice with the mGluR antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (Figure 3B) resulted in suppression of the audiogenic seizure phenotype (106) and rescue of dendritic spine morphology in the Fmr1 KO mouse (107).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [107]
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- Authors
- Su, T., Fan, H.-X., Jiang, T., Sun, W.-W., Den, W.-Y., Gao, M.-M., Chen, S.-Q., Zhao, Q.-H., & Yi, Y.-H.
- Affiliations
- Second Affiliated Hospital of Guangzhou Medical University (CN)
- Corresponding author
- Yi, Yong-Hong
- Venue
- Psychopharmacology
- Published
- 2010-12-23
- Volume
- 215
- Issue
- 2
- Pages
- 291-300
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- OpenAlex
- W2021455904
- Cited by
- 76
- References
- 49
- Citations by year
- 2024: 2 · 2023: 7 · 2022: 2 · 2021: 1 · 2020: 4 · 2019: 6 · 2018: 5 · 2017: 6 · 2016: 9 · 2015: 4 · 2014: 6 · 2013: 8 · 2012: 15
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- fragile X syndrome, Fmr1 knockout mice, group I metabotropic glutamate receptors, MPEP, dendritic spine morphology, spine length, cortical neurons, synaptic plasticity
- MeSH terms
- Age Factors, Analysis of Variance, Animals, Animals, Newborn, Benzopyrans, Cells, Cultured, Disease Models, Animal, Fragile X Syndrome, Hippocampus, Methoxyhydroxyphenylglycol, Mice, Inbred C57BL, Neural Inhibition, Neurons, Pyridines, Signal Transduction, Silver Staining, Receptors, Metabotropic Glutamate, Mice, Knockout, Dendritic Spines, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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