Synaptic vesicle dynamic changes in a model of fragile X

Abstract

BackgroundFragile X syndrome (FXS) is a single-gene disorder that is the most common heritable cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorders (ASD). FXS is caused by an expansion of trinucleotide repeats in the promoter region of the fragile X mental retardation gene (Fmr1). This leads to a lack of fragile X mental retardation protein (FMRP), which regulates translation of a wide range of messenger RNAs (mRNAs). The extent of expression level alterations of synaptic proteins affected by FMRP loss and their consequences on synaptic dynamics in FXS has not been fully investigated.MethodsHere, we used an Fmr1 knockout (KO) mouse model to investigate the molecular mechanisms underlying FXS by monitoring protein expression changes using shotgun label-free liquid-chromatography mass spectrometry (LC-MSE) in brain tissue and synaptosome fractions. FXS-associated candidate proteins were validated using selected reaction monitoring (SRM) in synaptosome fractions for targeted protein quantification. Furthermore, functional alterations in synaptic release and dynamics were evaluated using live-cell imaging, and interpretation of synaptic dynamics differences was investigated using electron microscopy.ResultsKey findings relate to altered levels of proteins involved in GABA-signalling, especially in the cerebellum. Further exploration using microscopy studies found reduced synaptic vesicle unloading of hippocampal neurons and increased vesicle unloading in cerebellar neurons, which suggests a general decrease of synaptic transmission.ConclusionsOur findings suggest that FMRP is a regulator of synaptic vesicle dynamics, which supports the role of FMRP in presynaptic functions. Taken together, these studies provide novel insights into the molecular changes associated with FXS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0080-1) contains supplementary material, which is available to authorized users.

Hypothalamic-pituitary-adrenal axis function in Fragile X Syndrome and its relationship to behaviour: A systematic review

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Impaired GABA Neural Circuits Are Critical for Fragile X Syndrome

“…Future research will examine that specific subunits of GABA receptor encode these vision information computations. And it is also worth noting that the role of GABA in the developing CNS is dynamic and variable between brain regions [ 40 , 43 , 46 ]. Another triggering idea is that impaired inhibition comes from activity-dependent synaptic plasticity alteration during developmentally critical periods [ 43 , 47 ].…”

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