Interval Timing is altered in male Nrxn1+/- mice: A Model of Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is characterised by impaired social interactions and communication and increased repetitive and stereotypical behaviour. Neuroimaging shows functional abnormalities in brain areas involved in temporal processing of autistic individuals, and autistic individuals show deficits in interval timing. Neurexin (NRXN) mutations have been identified in a wide variety of neuropsychiatric disorders, including ASD, and Nrxn1+/- mice possess a mutation that disrupts the , {beta}, and {gamma} isoforms of Nrxn1, a gene involved in synapse structure. We investigated the interval timing abilities of the Nrxn1+/- mouse model of ASD in the peak interval procedure using a 15-second target interval and compared their performance with that of Nrxn1+/+ and Nrxn1{Delta}S5/- rescue mice. Two-month-old male Nrxn1+/+ (C57BL/6J), Nrxn1+/-, and Nrxn1{Delta}S5/-, mice were trained to obtain sucrose liquid rewards 15s after the onset of a discriminative stimulus (discrete fixed-interval training), and their timing responses were tested in non-reinforced probe trials. Our analysis of responses in individual trials revealed that Nrxn1+/- mice had overall earlier timing responses. This difference was manifested as earlier termination of responding in terms of the response curves. These findings are consistent with leftward shifts observed with experimental animal models of ASD. In conclusion, we believe that these results are indicative of a biased long-term memory in the Nrxn1+/- mouse model of ASD and may capture the timing deficit observed in autistic individuals. Lay SummaryNeurexins help nerve cells connect and communicate with each other, and changes in these genes are often seen in people with autism. Mice with a change in their neurexin 1 gene, called Nrxn1+/- mice, show autism-like behaviours. In a test that involves judging time, these mice respond early, similar to some people with autism. This study helps develop our understanding of how interval timing is affected in ASD.