Evaluation of the neuroactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism
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Abnormalities in excitatory/inhibitory neurotransmission are hypothesized to contribute to autism spectrum disorder (ASD) etiology. BTBR T + Itpr3 tf /J (BTBR), an inbred mouse strain, displays social deficits and repetitive self-grooming, offering face validity to ASD diagnostic symptoms. Reduced GABAergic neurotransmission in BTBR suggests that GABAA receptor positive allosteric modulators (PAMs) could improve ASD-relevant BTBR phenotypes. The neuroactive steroid ganaxolone acts as a PAM, displaying anticonvulsant properties in rodent epilepsy models and an anxiolytic-like profile in the elevated plus-maze.
We evaluated ganaxolone in BTBR and C57BL/6J mice in standardized assays for sociability and repetitive behaviors. Open field and anxiety-related behaviors were tested as internal controls and for comparison with the existing neuroactive steroid literature.
Ganaxolone improved aspects of social approach and reciprocal social interactions in BTBR, with no effect on repetitive self-grooming, and no detrimental effects in C57BL/6J. Ganaxolone increased overall exploratory activity in BTBR and C57BL/6J in the open field, social approach, and elevated plus-maze, introducing a confound for the interpretation of social improvements. Allopregnanolone and diazepam similarly increased total entries in the elevated plus-maze, indicating that behavioral activation may be a general property of GABAA receptor PAMs in these strains.
Ganaxolone shows promise for improving sociability. In addition, ganaxolone, as well as other GABAA receptor PAMs, enhanced overall BTBR activity. The translational implications of specific sociability improvements and nonspecific behavioral activation by ganaxolone in the BTBR model remain to be determined. Future studies to explore whether PAMs provide a novel profile with unique benefits for ASD treatment will be worthwhile.
KeywordsAutism spectrum disorder Neuroactive steroid Ganaxolone Allopregnanolone Diazepam Anxiety Sociability Social approach Repetitive behaviors Open field
This work was supported by the UC Davis MIND Institute, the Autism Research Training Program (NIH/NIMH Grant T32 MH073124-10, Interdisciplinary Training for Autism Researchers), and the MIND Institute Intellectual and Developmental Disabilities Research Center (U54 HD079125). We thank Lisa Olsen in the Rogawski lab for her kind assistance in providing compounds and vehicles. In addition, we thank Dr. Jill Silverman, Dr. Mu Yang, Michael Pride, and Jane Hayes, UC Davis MIND Institute investigators in the Crawley lab, for their training on specific methods used by Dr. Kazdoba in the behavioral assays and statistical analyses of the data.
Compliance with ethical standards
All procedures were conducted in compliance with the NIH Guidelines for the Care and Use of Laboratory Animals and approved by the UC Davis Institutional Animal Care and Use Committee.
Conflict of interest
Dr. Hagerman has received funding from the Department of Defense and from Marinus Pharmaceuticals to study ganaxolone in a controlled trial in fragile X syndrome, both with and without autism. Dr. Rogawski is a consultant to Sage Therapeutics. Drs. Kazdoba, Zolkowska, and Crawley declare that they have no competing interests.
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