Abstract
Dopamine receptors and related signaling pathways have long been implicated in pathophysiology and treatment of mental illnesses, including schizophrenia and bipolar disorder. Dopamine signaling may impact neuronal activity by modulation of glutamate neurotransmission. Recent evidence indicates a direct and/or indirect involvement of fragile X-related family proteins (FXR) in the regulation and mediation of dopamine receptor functions. FXRs consists of fragile X mental retardation protein 1 (Fmr1/FMRP) and its autosomal homologs Fxr1 and Fxr2. These RNA-binding proteins are enriched in the brain. Loss of function mutation in human FMR1 is the major genetic contributor to Fragile X mental retardation syndrome. Therefore, the role of FXR proteins has mostly been studied in the context of autism spectrum disorders. However, recent genome-wide association studies have linked this family to schizophrenia, bipolar disorders, and mood regulation pointing toward a broader involvement in mental illnesses. FXR family proteins play an important role in the regulation of glutamate-mediated neuronal activity and plasticity. Here, we discuss the brain-specific functions of FXR family proteins by focusing on the regulation of dopamine receptor functions, ionotropic glutamate receptors-mediated synaptic plasticity and contribution to mental illnesses. Based on recent evidence, we propose that FXR proteins are potential integrators of dopamine signaling and ionotropic glutamate transmission.
Highlights
The neurotransmitter dopamine is involved in the regulation of several behavioral dimensions including locomotion, reward, affect, mood, and cognitive functions
The micro-RNA that is the most significantly associated to schizophrenia Mir137 has been shown to inhibit the expression of the fragile X mental retardation syndrome-related protein 1 (Fxr1) negative regulator Gsk3β by acting on the 3 untranslated region (UTR) of the GSK3B mRNA (Thomas et al, 2017)
A possible contribution to the disease may be via alterations in splicing of Fxr1 with subsequent changes in the regulation of microRNAs and their targets such as the D2 receptor mRNAs
Summary
The neurotransmitter dopamine is involved in the regulation of several behavioral dimensions including locomotion, reward, affect, mood, and cognitive functions. Recent studies point toward possible direct or indirect implications of FXR family proteins in dopamine receptor regulation and signaling. We explore the possible contribution of FXR proteins to the integration of dopamine and ionotropic receptor-mediated glutamate signaling in the broader context of adult onset mental disorders and addiction. Immunolabeling revealed widespread expression of Fxr, Fxr, and Fmr in fetal and adult human and mouse brains. These proteins are mostly localized to the cytoplasm and proximal dendrites of neurons. From a functional point of view, young mice lacking Fmr or both Fxr and Fmr display altered basal transmission, paired-pulse facilitation, and protein synthesis-dependent late-phase LTP (L-LTP) These parameters are unaffected at all ages in Fxr KO mice. GluA1/GluA2 containing to homomeric GluA1 AMPA receptors (Khlghatyan et al, 2018)
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