Abnormal behaviours relevant to neurodevelopmental disorders in Kirrel3-knockout mice.

Abstract

In the nervous system, Kirrel3 is involved in neuronal migration, axonal fasciculation, and synapse formation. Recently, genetic links have been reported between mutations in the KIRREL3 gene and increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability. To elucidate the causal relationship between KIRREL3 deficiency and behavioural abnormalities relevant to neurodevelopmental disorders, we generated global Kirrel3-knockout (Kirrel3) mice and investigated the detailed behavioural phenotypes. In the three-chambered social approach test, Kirrel3mice displayed a significant preference for a mouse over a non-social object but no significant preference for a stranger mouse over a familiar mouse. Ultrasonic communications, including pup-to-mother calls, male-female courtship vocalisation and resident responses to intruder, were significantly impaired in Kirrel3mice. Significant increases in locomotor activity and repetitive rearing were also observed in Kirrel3mice. Furthermore, the performance of Kirrel3mice in the rotarod test was significantly better than that of wild-type mice. In the acoustic startle test, Kirrel3mice were significantly hypersensitive to acoustic stimuli. Anxiety-related behaviours and spatial or fear memory acquisition were normal in Kirrel3mice. These findings suggest that Kirrel3mice exhibit autistic-like behaviours, including social and communicative deficits, repetitive behaviours, and sensory abnormalities, as well as hyperactivity.