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Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice
Femke M S de Vrij1, Josien Levenga, Herma C van der Linde
1Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
Abstract:
Lack of fragile X mental retardation protein (FMRP) causes Fragile X Syndrome, the most common form of inherited mental retardation. FMRP is an RNA-binding protein and is a component of messenger ribonucleoprotein complexes, associated with brain polyribosomes, including dendritic polysomes. FMRP is therefore thought to be involved in translational control of specific mRNAs at synaptic sites. In mice lacking FMRP, protein synthesis-dependent synaptic plasticity is altered and structural malformations of dendritic protrusions occur. One hypothesized cause of the disease mechanism is based on exaggerated group I mGluR receptor activation. In this study, we examined the effect of the mGluR5 antagonist MPEP on Fragile X related behavior in Fmr1 KO mice. Our results demonstrate a clear defect in prepulse inhibition of startle in Fmr1 KO mice, that could be rescued by MPEP. Moreover, we show for the first time a structural rescue of Fragile X related protrusion morphology with two independent mGluR5 antagonists.
Insights
Fragile X Syndrome, caused by lacking fragile X mental retardation protein (FMRP), shows behavioral and structural defects. Treatment with an mGluR5 antagonist rescued these Fragile X related issues in mice.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Fragile X Syndrome (FXS) is the most common inherited intellectual disability, caused by the absence of fragile X mental retardation protein (FMRP).
- FMRP, an RNA-binding protein, is crucial for translational control of mRNAs at synapses, impacting synaptic plasticity and dendritic structure.
- Exaggerated group I metabotropic glutamate receptor 5 (mGluR5) activation is a hypothesized mechanism underlying FXS pathology.
Purpose of the Study:
- To investigate the therapeutic potential of mGluR5 antagonists in ameliorating FXS-related behavioral and structural abnormalities.
- To assess the effect of MPEP, an mGluR5 antagonist, on prepulse inhibition of startle and dendritic morphology in Fmr1 knockout (KO) mice.
Main Methods:
- Utilized Fmr1 KO mice, a model for FXS.
- Administered the mGluR5 antagonist MPEP to Fmr1 KO mice.
- Assessed behavioral phenotypes, specifically prepulse inhibition of startle.
- Examined dendritic protrusion morphology using mGluR5 antagonists.
Main Results:
- Fmr1 KO mice exhibited a significant deficit in prepulse inhibition of startle.
- MPEP administration successfully rescued the prepulse inhibition deficit in Fmr1 KO mice.
- Two independent mGluR5 antagonists demonstrated a structural rescue of dendritic protrusion morphology in Fmr1 KO mice.
Conclusions:
- mGluR5 receptor overactivation contributes to behavioral and structural deficits in FXS.
- mGluR5 antagonists represent a promising therapeutic strategy for treating Fragile X Syndrome.
- Targeting mGluR5 signaling offers a potential pathway for rescuing synaptic and behavioral abnormalities in FXS.
