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Astroglial FMRP modulates synaptic signaling and behavior phenotypes in FXS mouse model
- Source :
- GliaREFERENCES. 69(3)
- Publication Year :
- 2020
-
Abstract
- Fragile X syndrome (FXS) is one of the most common inherited intellectual disability (ID) disorders, in which the loss of FMRP protein induces a range of cellular signaling changes primarily through excess protein synthesis. Although neuron-centered molecular and cellular events underlying FXS have been characterized, how different CNS cell types are involved in typical FXS synaptic signaling changes and behavioral phenotypes is largely unknown. Recent evidence suggests that selective loss of astroglial FMRP is able to dysregulate glutamate uptake, increase spine density, and impair motor-skill learning. Here we investigated the effect of astroglial FMRP on synaptic signaling and FXS-related behavioral and learning phenotypes in astroglial Fmr1 cKO and cON mice in which FMRP expression is selectively diminished or restored in astroglia. We found that selective loss of astroglial FMRP contributes to cortical hyperexcitability by enhancing NMDAR-mediated evoked but not spontaneous miniEPSCs and elongating cortical UP state duration. Selective loss of astroglial FMRP is also sufficient to increase locomotor hyperactivity, significantly diminish social novelty preference, and induce memory acquisition and extinction deficits in astroglial Fmr1 cKO mice. Importantly, re-expression of astroglial FMRP is able to significantly rescue the hyperactivity (evoked NMDAR response, UP state duration, and open field test) and social novelty preference in astroglial Fmr1 cON mice. These results demonstrate a profound role of astroglial FMRP in the evoked synaptic signaling, spontaneously occurring cortical UP states, and FXS-related behavioral and learning phenotypes and provide important new insights in the cell type consideration for the FMRP reactivation strategy.
- Subjects :
- 0301 basic medicine
Cell signaling
Cell type
congenital, hereditary, and neonatal diseases and abnormalities
Biology
Receptors, N-Methyl-D-Aspartate
Open field
03 medical and health sciences
Cellular and Molecular Neuroscience
Fragile X Mental Retardation Protein
Mice
0302 clinical medicine
medicine
Animals
medicine.disease
FMR1
Phenotype
nervous system diseases
Fragile X syndrome
Disease Models, Animal
030104 developmental biology
Neurology
Astrocytes
Fragile X Syndrome
NMDA receptor
Synaptic signaling
Neuroscience
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 10981136
- Volume :
- 69
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- GliaREFERENCES
- Accession number :
- edsair.doi.dedup.....db9e4d4e9f8a898035daeecade9db407