Sydney Collis

Introduction. Fragile X is a heritable disease resulting from the loss of the Fragile X Mental Retardation Protein or FMRP and is characterized by large variation of intellectual disorders, however there is no current effective treatment for the cumulative cognitive and social interaction deficits of FXS.¹ Previous therapeutic research has focused on mGluR, an excitatory neurotransmitter, as the potential target, but with no significant promise in human trials, the focused has shifted towards the GABA receptor.^{1, 4, 5} This review aims to evaluate specific subunits of the GABA_A receptor as a potential therapeutic target for cortical hyperexcitability in FXS. Methods. To test cortical excitatory and inhibitory mechanisms, Transcranial magnetic stimulation was used to stimulate different areas of control of FMR1 KO mice brains and access short-interval intracortical inhibition (GABA_A) and long-interval inhibition (GABA_B).⁴ Immunohistochemistry was utilized to analyze the presence of specific subunits of the GABA_A receptor and Cross-linking experiments and Western blots analysis were performed to analyze the expression of the delta subunit in FMR1 KO mice compared to controls.⁵ Lastly, Gaboxadol, a selective delta-subunit GABA_A receptor agonist was given in a randomized, double-blind, phase 2a study to 32 FXS boys BID, TD, or QID and their behaviors were assessed over a 12 week period using standardized questionnaires completed by their caregivers.⁶ Results. TMS showed that FXS patients exhibit decreased GABA_A inhibition, and increased GABA_B inhibition and intracortical facilitation compared to controls.⁴ Immunogold labeling found lower expression of the GABA_A delta subunit in FXS KO mice implying that reduced tonic inhibition may be relation to surface expression of the delta subunit.⁵ PCR tests showed a decreased level of GABA_A subunit expression, specifically in subunits alpha2, beta1 and delta. ⁷ Additionally, it was found that 60% of Gaboxadol study participants had minimal improvement and 40% being much improved at week 12, with the highest efficacy among the BID group.⁶ Conclusion. GABA_A is the mediator of cortical hyperexcitability in Fragile X syndrome and the delta subunit specifically has reduced expression.⁴ Results point to altered postsynaptic mechanisms of inhibition in GABA_A subunits as possible mechanism for disease.⁷ Delta subunit agonists, such as Gaboxadol should continue to be explored as potential therapeutic targets for hyperexcitability symptoms in FXS.⁶

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