FMRP's Striatal Function: Implications for Synaptic Plasticity, Fragile X Syndrome, and Substance Use Disorders

Abstract

The fragile X mental retardation protein (FMRP), an RNA-binding protein that mediates the transport, stability, and translation of hundreds of RNAs, is critically involved in regulating synaptic function. Loss of FMRP, as in fragile X syndrome (FXS), is a leading monogenic cause of autism spectrum disorders (ASDs) and results in altered structural and functional plasticity, widely described in hippocampus and cortex. Though FXS is characterized in part by impaired social interaction and development of repetitive or stereotyped behaviors, both of which are influenced by striatal activity, few studies have investigated FXS or FMRP in the context of striatal function. In the first set of experiments described here, we find that striatal medium spiny neurons (MSNs) lacking FMRP have significant deficits in dendritic spine density and synaptic puncta at 14 days in vitro. We also find FMRP’s KH2 and RGG RNA-binding domains are required for normal elimination of PSD95, and considering previous findings, our results suggest distinct regional and/or cell type-specific roles for FMRP in regulating synapse structure. In our second set of experiments, we demonstrate that Fmr1 knockout (KO) mice, lacking FMRP, have enhanced repetitive behaviors compared to WT mice across multiple assays but fail to demonstrate perseverative choices observed in other mouse models for ASDs. We also find a basal deficit in dendritic spine density in MSNs from the dorsal lateral striatum of KO mice and identify a role for FMRP in cocaine-induced dendritic plasticity, potentially facilitating refinement of this brain circuit in response to drug reinforcement. In the final set of experiments described here, we find that FMRP promotes adjustments in responding for cocaine in an intravenous self-administration task, particularly those requiring increased effort, ultimately supporting the preservation of reinforcement level. Collectively, this work increases our understanding of FMRP’s striatal function, highlighting regional- and cell type-specific differences, which may be critical to consider in the development of successful treatments for FXS. Further, we provide evidence that FMRP mediates normal behavioral, as well as striatal synaptic, responses to cocaine exposure, an avenue of investigation that has the potential to identify new targets for therapeutic intervention in substance use disorders.