Evaluation of the neuroactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism

Abstract

Rationale Abnormalities in excitatory/inhibitory neurotransmission are hypothesized to contribute to autism spectrum disorder (ASD) etiology. 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. Objectives 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. Results 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. Conclusions 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 non-specific behavioral activation by ganaxolone in the BTBR model remains to be determined. Future studies to explore whether PAMs provide a novel profile with unique benefits for ASD treatment will be worthwhile.

Hypothesis‐driven investigations of diverse pharmacological targets in two mouse models of autism

“…In the TrkB Shank3B cohort, water maze was conducted last. Our previous studies with B6, BTBR, and Shank3 B had revealed similar scores in males and females on the behavioral assays used in the present studies [Yang et al, ; McFarlane et al, ; Silverman et al, , ; Kazdoba et al, ; Dhamne et al, ], therefore both males and females were approximately equally represented in the Ns for each cohort, with the exception of male–female reciprocal social interactions in which only the males were tested. Breeding were designed to yield N = 12–15 per treatment group, to provide sufficient power to detect drug effects, as confirmed in previous studies [Silverman et al, , ; Silverman, Oliver, Karras, Gastrell, & Crawley, ; Kazdoba et al, ; Stoppel et al, ].…”

“…Animal models that incorporate mutations in risk genes for autism, and display behaviors with relevance to the diagnostic symptoms of autism, can approximate but never fully recapitulate all components of the human syndrome. Mutant mouse models offer translational tools to investigate potential pharmacological targets for personalized treatments of the core symptoms of autism [Spooren, Lindemann, Ghosh, & Santarelli, ; Kazdoba et al, ; Chadman, ].…”

Recent developments in understanding the role of the gut microbiota in brain health and disease

“…Genetic animal models of autism allow us to investigate the relationship between the host genome and the microbiota. The BTBR animal model of autism displays a robust autistic‐like phenotype, with deficits in social behaviors, repetitive behaviors, and anxiety‐related behaviors frequently reported . Recently, it was demonstrated that BTBR mice display a reduction in the Firmicutes/Bacteroidetes ratio, along with increases in the abundance of species such as A. mucinphilia and reductions in Bifidobacterium spp , suggestive of microbiota dysregulation .…”

Corticotropin‐releasing factor receptor 2‐deficiency eliminates social behaviour deficits and vulnerability induced by cocaine

“…Moreover, since three-chamber performance is considered a yes-or-no result, within each experimental group, time spent by the subject mouse exploring the unfamiliar mouse or the object, the novel or the familiar mouse, during the sociability or the SNP tests, respectively, was compared using Student's paired t-test, as previously suggested (Silverman et al, 2015;Kazdoba et al, 2016). To prevent initial side preference from biasing the results, only animals exploring each side compartment of the threechamber apparatus for no more than 70% of the 10 min habituation phase were included in the study (inclusion criterion).…”