Social behavior in prepubertal neurexin 1α deficient rats: A model of neurodevelopmental disorders.

Abstract

Loss-of-function mutations in the synaptic protein neurexin1α (NRXN1α) are associated with several neurodevelopmental disorders, including autism spectrum disorder (ASD), schizophrenia, and attentiondeficit hyperactivity disorder (ADHD), and many of these disorders are defined by core deficits in social cognition. Mouse models of Nrxn1α deficiency are not amenable to studying aspects of social cognition because, in general, mice do not engage in complex social interactions such as social play or prosocial helping behaviors. Rats, on the contrary, engage in these complex, well-characterized social behaviors. Using the Nrxn1 tm1Sage Sprague Dawley rat, we tested a range of cognitive and social behaviors in juveniles with haplo-or biallelic Nrxn1α mutation. We found a deficit in ultrasonic vocalizations (USVs) of male and female neonatal rats with Nrxn1α deficiency. A male-specific deficit in social play was observed in Nrxn1αdeficient juveniles, although sociability and social discrimination were unaltered. Nurturing behavior induced by exposure to pups was enhanced in male and female juveniles with biallelic Nrxn1α mutation. Performance in tasks of prosocial helping behavior and food retrieval indicated severe deficits in learning and cognition in juveniles with biallelic Nrxn1α mutation, and a less severe deficit in haploinsufficient rats, although Pavlovian learning was altered only in haploinsufficient males. We also observed a male-specific increase in mobility and object investigation in juveniles with complete Nrxn1α deficiency. Together, these observations more fully characterize the Nrxn1 tm1Sage Sprague Dawley rat as a model for Nrxn1α-related neurodevelopmental disorders, and support a rationale for the juvenile rat as a more appropriate model for disorders that involve core deficits in complex social behaviors.

Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder

“…Mice lacking Nrxn1 exhibit deficits in core symptoms related to ASD. Specifically, Nrxn1α mutants display deficits in the social domain including increased social preference, decreased social investigation, decreased social interaction, and increased aggression [ 35 , 46 , 47 , 48 ]. Furthermore, they show stereotypic and repetitive behaviors such as increased grooming, impaired nest-building, altered novelty responsiveness, and habituation [ 31 , 35 , 38 ].…”

“…Furthermore, they show stereotypic and repetitive behaviors such as increased grooming, impaired nest-building, altered novelty responsiveness, and habituation [ 31 , 35 , 38 ]. In addition, several behaviors were reported that relate to ASD comorbidities including deficits in learning and cognition, locomotor activity, motor performance, award processing, and anxiety-like behaviors [ 31 , 35 , 36 , 38 , 46 , 47 , 48 , 49 ]. Although the social, stereotyped, and repetitive behaviors are commonly studied, sensory behaviors have received less attention in this model.…”

“…However, Nrxn1 knockout mice show increased responses to auditory stimuli, seen by increases in startle responses to 80–100 dB auditory stimuli and increased startle response to 120 dB startle, indicating altered auditory sensitivity [ 31 , 36 ] In addition, while acoustic pre-pulse inhibition does not seem to be affected in heterozygous knockout mice or rat model [ 46 ], homozygous knockout mice display a decrease in pre-pulse inhibition [ 35 , 46 , 47 ]. Lastly, Nrxn1 knockout rats display decreased eye-blink conditioning, indicating altered cerebral sensory learning [ 48 ]. There was no indication of differences in olfaction, while other sensory domains, such as tactile and visual sensitivity, still remain to be investigated.…”

“…Monitoring the timing of the behavioral phenotypes could provide valuable information about sensitive windows in phenotype development. Multiple labs assessed social behavior during early life by measuring USVs in Nrnx1 -/- pups from postnatal day (PND) 2–12 [ 47 , 48 ]. They reported reduced ultrasonic vocalization in pups with alterations in the complexity of USVs, indicative of deficits in early communications in pups [ 2 ].…”

“…Other social impairments were also found in these models later during development, Shank3 -/- and Cntnap2 -/- mice juveniles display decreased social interactions around PND 21–25 [ 30 , 32 , 42 ]. Social behavior was also decreased at several moments during early adolescence in Nrxn1 knockout mice (PND 27–35) and late adolescence in Shank3 knockout mice (PND 42–56) [ 47 , 48 , 61 ]. In addition to social behavior, Armstrong et al also studied other behavioral phenotypes across developmental periods in Nrxn1 -/- and found delays in reaching developmental milestones in juvenile Nrxn1 knockout mice from PND 5–15 [ 47 ].…”