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The Fragile X Mental Retardation Protein Regulates Striatal Medium Spiny Neuron Synapse Density and Dendritic Spine
Jessica L Huebschman1,2, Kitzia S Corona1, Yuhong Guo1
1Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX, United States.
Abstract:
The fragile X mental retardation protein (FMRP), an RNA-binding protein that mediates the transport, stability, and translation of hundreds of brain RNAs, is critically involved in regulating synaptic function. Loss of FMRP, as in fragile X syndrome (FXS), is a leading monogenic cause of autism and results in altered structural and functional synaptic plasticity, widely described in the hippocampus and cortex. Though FXS is associated with hyperactivity, impaired social interaction, and the development of repetitive or stereotyped behaviors, all of which are influenced by striatal activity, few studies have investigated the function of FMRP here. Utilizing a cortical-striatal co-culture model, we find that striatal medium spiny neurons (MSNs) lacking FMRP fail to make normal increases in PSD95 expression over a short time period and have significant deficits in dendritic spine density and colocalized synaptic puncta at the later measured time point compared to wildtype (WT) MSNs. Acute expression of wtFMRP plasmid in Fmr1 KO co-cultures results in contrasting outcomes for these measures on MSNs at the more mature time point, reducing spine density across multiple spine types but making no significant changes in colocalized puncta. FMRP's KH2 and RGG RNA-binding domains are required for normal elimination of PSD95, and interruption of these domains slightly favors elimination of immature spine types. Further, KH2 is required for normal levels of colocalized puncta. Our data are largely consistent with a basal role for FMRP and its RNA-binding domains in striatal synapse stabilization on developing MSNs, and in light of previous findings, suggest distinct regional and/or cell type-specific roles for FMRP in regulating synapse structure.
Insights
Fragile X mental retardation protein (FMRP) loss impairs striatal synapse development in medium spiny neurons. FMRP
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Fragile X mental retardation protein (FMRP) regulates synaptic function and RNA processing in the brain.
- Loss of FMRP causes fragile X syndrome (FXS), a leading genetic cause of autism spectrum disorder (ASD).
- FXS is linked to altered synaptic plasticity in the hippocampus and cortex, but FMRP's role in the striatum is less understood.
Purpose of the Study:
- To investigate the function of FMRP in striatal medium spiny neurons (MSNs) using a cortical-striatal co-culture model.
- To determine the impact of FMRP deficiency on synaptic structure and protein expression in MSNs.
- To identify the specific RNA-binding domains of FMRP critical for its function in the striatum.
Main Methods:
- Utilized a cortical-striatal co-culture model to study FMRP function in MSNs.
- Assessed PSD95 expression, dendritic spine density, and synaptic puncta in wildtype (WT) and FMRP-deficient (Fmr1 KO) MSNs.
- Investigated the role of FMRP's KH2 and RGG RNA-binding domains by analyzing outcomes after plasmid expression in KO co-cultures.
Main Results:
- MSNs lacking FMRP showed deficits in PSD95 expression, dendritic spine density, and synaptic puncta.
- Acute expression of wildtype FMRP in Fmr1 KO co-cultures partially rescued these deficits, with contrasting effects on spine density and puncta.
- FMRP's KH2 and RGG domains were essential for normal PSD95 elimination and synaptic puncta levels, with KH2 also crucial for colocalized puncta.
Conclusions:
- FMRP plays a basal role in stabilizing striatal synapses on developing MSNs.
- Specific RNA-binding domains (KH2 and RGG) are critical for FMRP's function in regulating synapse structure.
- Findings suggest distinct regional and cell-type-specific roles for FMRP in regulating synaptic organization.
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