Fragile X

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“Reducing glutamate signaling pays off in fragile X” https://www.nature.com/nm/journal/v14/n3/full/nm0308-249.html

“This has become a long-standing unanswered question in the fragile X field, which is also relevant to autism pathogenesis. Our current study generated astrocyte-specific Fmr1 conditional knock-out and restoration mice, and provided compelling evidence that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, likely through the dysregulated astroglial glutamate transporter GLT1 expression and impaired glutamate uptake. These results demonstrate previously undescribed astrocyte-mediated mechanisms in the pathogenesis of FXS.” https://www.ncbi.nlm.nih.gov/pubmed/27383586

“We observed significantly reduced levels of protein for FMRP in adults with autism, significantly increased levels of protein for mGluR5 in children with autism and significantly increased levels of GFAP in adults and children with autism. We found no change in expression of GABRβ3. Our results for FMRP, mGluR5 and GFAP confirm our previous work in the cerebellar vermis of people with autism.” “These changes may be responsible for cognitive deficits and seizure disorder in people with autism.” https://molecularautism.biomedcentral.com/articles/10.1186/2040-2392-2-6

“This concept certainly resonates in the study of fragile X syndrome, a monogenic disorder with a striking hyperexcitability phenotype. Fragile X patients display hyperactivity, tactile defensiveness, multi-sensory hypersensitivity, a wide range of anxiety disorders, mood lability, aggression, and seizures in 20–30% of males.2 Animal models of fragile X recapitulate many of the human phenotypes, and electrophysiologic studies confirm hyperexcitability at the synaptic and circuit level.3 Much of the focus to date has been on glutamatergic dysfunction in fragile X, and how this might render the fragile X brain hyperexcitable. However, clinical trials of glutamatergic agents in human subjects with fragile X have been disappointing, leaving an unmet need for fragile X therapeutics.” “He et al. have found that the normal developmental switch from excitatory to inhibitory neurotransmission at GABAergic synapses is delayed and abnormally regulated in fragile X mice.7 How persistent these changes are later life in humans with fragile X remains unknown, but this type of polarity reversal could wreak havoc with the formation of inhibitory networks, and could complicate pharmacotherapy with GABAergic agents. Nonetheless, interest is clearly shifting to GABAA as a treatment target for fragile X.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614528/