Editors' ChoiceAutism Spectrum Disorder

Seizing control of fragile X syndrome

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Science Translational Medicine  01 Jan 2020:
Vol. 12, Issue 524, eaba2902
DOI: 10.1126/scitranslmed.aba2902

Abstract

Loss of Fmr1 in glutamatergic neurons of the inferior colliculus is responsible for audiogenic seizures in the fragile X syndrome mouse model.

In mouse models of fragile X syndrome (FXS), the most commonly identified genetic cause of autism, the audiogenic seizure (AGS) assay is a gold standard. AGSs model the hypersensitivity and seizures in FXS patients, and compounds that correct this phenotype in Fmr1 knockout (KO) mice have gone on to clinical trials.

In a recently published study, Gonzalez et al. identified the neural circuit underlying AGSs in Fmr1 KO mice using a comprehensive set of cell type–specific Fmr1 manipulations. Mice expressing the Cre gene in specific neuronal populations were mated with both Fmr1-cOFF or Fmr1-cON mice to delete or re-express Fmr1 in specific neuronal and glial populations. Testing for the incidence and severity of seizures upon exposure to a >110 dB loud alarm in these different mouse strains identified which cell types were involved in AGS generation. Given the hyperexcitability seen in glutamatergic cortical neurons of the Fmr1 KO, Gonzalez et al. first manipulated Fmr1 in these neurons to observe the impact on AGS. Surprisingly, ablation of Fmr1 in cortical cells did not induce the AGS phenotype in wild-type mice, nor did Fmr1 re-expression prevent the occurrence of AGS in global Fmr1 KO mice. However, when the investigators depleted Fmr1 from the more widely expressed VGlut2-positive glutamatergic neurons, the results showed a notable increase in AGS, suggesting that subcortical structures are necessary for AGS development. Further interrogation revealed that deletion of Fmr1 in VGlut2-positive neurons of the inferior colliculus, a subcortical region that relays auditory information, is necessary to reproduce the AGS phenotype.

The identification of the neuron population driving the most robust behavioral phenotype in Fmr1 KO mice is an important contribution to translational studies of FXS. Now researchers can identify the cellular consequences of Fmr1 loss in these neurons that drive hyper-responsiveness and seizure generation, potentially identifying new targeted treatments. Moreover, further interrogation of these neurons in animals treated with validated pharmacological strategies will reveal essential information about the mechanism of action. Although the lack of in-depth mechanistic characterization is a limitation of this work that will need to be explored in future studies, the results of this study are clearly of great importance for seizing new options to understand and treat FXS.

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