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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number678090
JournalFrontiers in Psychiatry
Volume12
DOIs
StatePublished - May 21 2021

Keywords

  • audiogenic seizures
  • EEG
  • FMRP
  • Fragile X syndrome
  • FXS
  • GABA
  • novel object recognition
  • UP states

ASJC Scopus subject areas

  • Psychiatry and Mental health

Fingerprint

Dive into the research topics of 'GABA<sub>A</sub> Alpha 2,3 Modulation Improves Select Phenotypes in a Mouse Model of Fragile X Syndrome'. Together they form a unique fingerprint.

Cite this