Reversal of social deficits by subchronic oxytocin in two autism mouse models

Abstract

Social deficits are a hallmark feature of autism spectrum disorder (ASD) and related developmental syndromes. Although there is no standard treatment for social dysfunction, clinical studies have identified oxytocin as a potential therapeutic with prosocial efficacy. We have previously reported that peripheral oxytocin treatment can increase sociability and ameliorate repetitive stereotypy in adolescent mice from the C58/J model of ASD-like behavior. In the present study, we determined that prosocial oxytocin effects were not limited to the adolescent period, since C58/J mice, tested in adulthood, demonstrated significant social preference up to 2 weeks following subchronic oxytocin treatment. Oxytocin was also evaluated in adult mice with underexpression of the N-methyl-D-aspartate receptor NR1 subunit (encoded by Grin1), a genetic model of autism- and schizophrenia- like behavior. Subchronic oxytocin had striking prosocial efficacy in male Grin1 knockdown mice; in contrast, chronic regimens with clozapine (66 mg/kg/day) or risperidone (2 mg/kg/day) failed to reverse deficits in sociability. Neither the subchronic oxytocin regimen, nor chronic treatment with clozapine or risperidone, reversed impaired prepulse inhibition in the Grin1 knockdown mice. Overall, these studies demonstrate oxytocin can enhance sociability in mouse models with divergent genotypes and behavioral profiles, adding to the evidence that this neurohormone could have therapeutic prosocial efficacy across a spectrum of developmental disorders.

Neonatal Oxytocin Treatment Ameliorates Autistic-Like Behaviors and Oxytocin Deficiency in Valproic Acid-Induced Rat Model of Autism

“…Oxt ( Ferguson et al, 2000 ; Ferguson et al, 2001 ) or Oxtr ( Sala et al, 2011 ; Pobbe et al, 2012a , b ) knockout (KO) mice have been reported to exhibit less social communication and interaction, along with impaired social cognitive memory and other altered behaviors relevant to ASD ( Zhang et al, 2017 ). Central infusion or peripheral injection of OXT has been shown to promote social approach ( Lukas et al, 2011 ; Teng et al, 2016 ), pair bonding ( Bales and Carter, 2003 ; Bales et al, 2007 ; Ross et al, 2009 ), and social memory ( Popik and van Ree, 1991 ; Benelli et al, 1995 ) in rodents.…”

Parvalbumin Cell Ablation of NMDA-R1 Leads to Altered Phase, But Not Amplitude, of Gamma-Band Cross-Frequency Coupling

“…These NR1 neoÀ/À mice may demonstrate behavioral phenotypes associated with ASD, including perturbed sociality (Barkus et al, 2012;Gandal et al, 2012a,b). Of note, this perturbed sociability may be selective to males (Barkus et al, 2012) and reversible with oxytocin administration (Teng et al, 2016). Deficits in sociability are absent when the NR1 neoÀ/À knockout is induced in adult mice (Belforte et al, 2010).…”

Environmental Enrichment Intervention in Animal Models of Autism

“…Some inbred mouse strains expressing phenotypes relevant to autism are also used as autism models. Several studies revealed that C58/J mice displayed increased activity and repetitive behaviors, as well as less social approach in the three-chamber test [48][49][50][51] . Environmental enrichment (rearing in enriched cages) was reported to reduce repetitive behaviors and improve reversal learning in this strain [52,53] .…”