Mouse Models of Autism Phenotypes As Preclinical Screening Platforms for Novel Oxytocinergic Compounds

Background: There is emerging evidence that oxytocin (OT) treatment can improve social deficits and repetitive behavior in autism spectrum disorders (ASDs). However, administration of the neuropeptide, which has a short plasma half-life and poor ability to penetrate the blood-brain barrier, is a problematic issue for clinical use. We have recently initiated a drug development program to identify novel, highly selective, non-peptide OT receptor (OTR) agonists. These efforts would be accelerated by animal models to screen drug candidates for efficacy against ASD-relevant phenotypes.

Objectives: Validate mouse models for preclinical screening of compounds that target the OT pathway, in order to facilitate the development of therapeutics for core ASD symptoms.

Methods: BALB/cByJ and C58/J are well-characterized inbred mouse strains that exhibit behavioral phenotypes relevant to ASD. To validate these models as preclinical screens, mice were tested for OT effects on sociability in a three-chamber task and perseverative responses in a marble-burying assay. C58/J was also examined for OT effects on repetitive behavior and open field activity. These screening platforms were then used to evaluate Compound 39 (a synthetic, non-peptide OTR agonist).

Results: The acute OT regimen did not increase sociability in BALB/cByJ. However, the sub-chronic OT regimen (i.e. four intraperitoneal injections across 7-8 days) had significant prosocial effects in both BALB/cByJ and C58/J. Increased sociability was observed 24 hr following the final OT dose in BALB/cByJ, while prosocial effects of OT emerged 1-2 weeks post-treatment in C58/J. An acute OT regimen decreased motor stereotypy in C58/J, at a dose that did not produce sedative or anxiolytic-like effects in open field testing. Similarly, acute OT treatment led to significant reductions in marble-burying by BALB/cByJ. Consistent with previous research, Compound 39 produced some OT-like effects; however, the drug had no effect on sociability.

Conclusions: These studies show that OT reverses social deficits in mouse models of ASD, dependent on dose regimen and genotype. Furthermore, acute OT decreases abnormal repetitive behavior in C58/J and marble-burying in BALB/cByJ. These findings provide validation of the BALB/cByJ and C58/J models as valuable platforms for screening novel drugs for intervention in ASDs, and for elucidating the mechanisms contributing to prosocial and other beneficial effects of OT.