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.
Highlights
The fragile X mental retardation protein (FMRP) is an RNA-binding protein encoded by the Fmr1 gene, which regulates the transport, stability, and translation of hundreds of brain RNAs, many of which are critically involved in synaptic function
Striatal WT medium spiny neurons (MSNs) show a significant increase in synapse count, associated with an increase in postsynaptic marker (PSD95) expression, which emerges between day in vitro (DIV) 10 and 14
During the same time frame, Fmr1 KO MSNs fail to increase PSD95 expression and at DIV 14 show an overall deficit in spine density compared to WT MSNs
Summary
The fragile X mental retardation protein (FMRP) is an RNA-binding protein encoded by the Fmr gene, which regulates the transport, stability, and translation of hundreds of brain RNAs, many of which are critically involved in synaptic function. FMRP regulates numerous presynaptic activities, including translation-independent ion channel trafficking and stabilization, neurotransmitter release, and axon growth cone dynamics (Antar et al, 2006; Centonze et al, 2008; Deng et al, 2013; Ferron et al, 2020). While FMRP regulates localization of presynaptic voltage-gated calcium channels independently of new protein synthesis, mutations in the RGG RNA binding domain are sufficient to impair the protein-protein interactions necessary for this function (Ferron et al, 2020), highlighting a broader role for these domains in regulating synaptic plasticity
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