Abstract
Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability. It is produced by mutation of the Fmr1 gene that encodes for the Fragile Mental Retardation Protein (FMRP), an important RNA-binding protein that regulates the expression of multiple proteins located in neuronal synapses. Individuals with FXS exhibit abnormal sensory information processing frequently leading to hypersensitivity across sensory modalities and consequently a wide array of behavioral symptoms. Insects and mammals engage primarily their sense of smell to create proper representations of the external world and guide adequate decision-making processes. This feature in combination with the exquisitely organized neuronal circuits found throughout the olfactory system (OS) and the wide expression of FMRP in brain regions that process olfactory information makes it an ideal model to study sensory alterations in FXS models. In the last decade several groups have taken advantage of these features and have used the OS of fruit fly and rodents to understand neuronal alteration giving rise to sensory perception issues. In this review article, we will discuss molecular, morphological and physiological aspects of the olfactory information processing in FXS models. We will highlight the decreased inhibitory/excitatory synaptic balance and the diminished synaptic plasticity found in this system resulting in behavioral alteration of individuals in the presence of odorant stimuli.
Highlights
Fragile X syndrome (FXS) is one of the most common causes of inherited intellectual disability and the most common monogenetic cause of autism
The Fragile Mental Retardation Protein (FMRP) is a selective RNA-binding protein that regulates the transcription of 4% of the total proteins found in the mammalian brain (Ashley et al, 1993), where its primary function is to repress local protein translation of specific mRNAs at dendrites in an activity-dependent manner, down-regulating the synthesis of proteins involved in synaptic plasticity and function (Brown et al, 2001; Darnell and Klann, 2013; Sidorov et al, 2013; Suhl and Hoeffer, 2017; Bagni and Zukin, 2019)
In the mutant dfmr1− fly, the branch length is already diminished in basal conditions and the pyrrolidine-induced structural change reduction is not observed (Doll et al, 2017). These results suggest that FMRP plays an important role in synapse formation and that the deficits in activity-dependent structural plasticity observed in granule cells (GCs) could mediate in part the cognitive defects found in the experimental FXS models
Summary
Fragile X syndrome (FXS) is one of the most common causes of inherited intellectual disability and the most common monogenetic cause of autism. FXG are structures that comprise proteins, ribosomes and mRNA and can be found only in a subset of brain regions including the axons of OSNs and in the glomeruli neuropil in the OB, suggesting that FMRP could have a post-synaptic role regulating post-synaptic protein translation and be involved in plastic pre-synaptic olfactory processes (Christie et al, 2009; Akins et al, 2012; Korsak et al, 2017) as have been shown in hippocampal pyramidal neurons (Deng et al, 2013; Myrick et al, 2015).
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