GABAA Alpha 2,3 Modulation Improves Select Phenotypes in a Mouse Model of Fragile X Syndrome.

Tori L Schaefer,Michael T Williams,Madison P Tomasek,Jay R Gibson,Emma V Parkins,Matthew H Davenport,Angela R White,Kimberly M Huber,Durgesh Tiwari,Lindsay M Grainger,Chandler K Robinson,Andrew Snider,Rishav Mukherjee,Amy A Ashworth,Craig A Erickson,Robert A Becker,Christina Gross

doi:10.3389/fpsyt.2021.678090

Abstract

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability. FXS is caused by functional loss of the Fragile X Protein (FXP), also known as Fragile X Mental Retardation Protein (FMRP). In humans and animal models, loss of FXP leads to sensory hypersensitivity, increased susceptibility to seizures and cortical hyperactivity. Several components of the GABAergic system, the major inhibitory system in the brain, are dysregulated in FXS, and thus modulation of GABAergic transmission was suggested and tested as a treatment strategy. However, so far, clinical trials using broad spectrum GABAA or GABAB receptor-specific agonists have not yielded broad improvement of FXS phenotypes in humans. Here, we tested a more selective strategy in Fmr1 knockout (KO) mice using the experimental drug BAER-101, which is a selective GABAA α2/α3 agonist. Our results suggest that BAER-101 reduces hyperexcitability of cortical circuits, partially corrects increased frequency-specific baseline cortical EEG power, reduces susceptibility to audiogenic seizures and improves novel object memory. Other Fmr1 KO-specific phenotypes were not improved by the drug, such as increased hippocampal dendritic spine density, open field activity and marble burying. Overall, this work shows that BAER-101 improves select phenotypes in Fmr1 KO mice and encourages further studies into the efficacy of GABAA-receptor subunit-selective agonists for the treatment of FXS.

Highlights

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and often associated with autism, anxiety, irritability, and attention deficit hyperactivity disorder [1]
Because BAER-101, as a GABA type A (GABAA) agonist, is expected to enhance inhibitory signaling, we assessed if the drug reduces hyperexcitable network activity in Fmr1 KO mice by testing its effect on neocortical UP states, cortical EEG abnormalities, and audiogenic seizures
These results suggest that selective GABAA modulation with BAER-101 reduces neocortical circuit hyperactivity in FXS

Summary

Introduction

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and often associated with autism, anxiety, irritability, and attention deficit hyperactivity disorder [1]. Many potential small molecule candidates have been tested in clinical studies [2,3,4], there is currently no effective approved treatment of FXS. FXS is caused by a trinucleotide (CGG) repeat expansion in the 5’UTR of the FMR1 gene leading to its transcriptional silencing and loss of a single protein, the Fragile X Protein (FXP), known as Fragile X Mental Retardation Protein (FMRP). Fmr knockout (KO) mice, the most frequently used animal model for FXS, display many phenotypes reminiscent of the human condition. They show, for example, hyperactivity, altered social preference, and impaired cognition, and are widely used to investigate pathological mechanisms of FXS and to preclinically test novel therapeutic strategies [6]

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