Engrailed-2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder.

摘要

Autism spectrum disorder (ASD) is an inheritable neurodevelopmental disorder. Core symptoms include social and communication deficits and restricted and repetitive motor patterns. Recent human genetic studies are consistent with the homeobox transcription factor, ENGRAILED 2 ( EN2), being an ASD susceptibility gene. En2 knockout mice (En-/-) display cerebellar neuropathological changes similar to what has been observed in the ASD brain. Therefore, we investigated whether En2-/- mice displayed abnormal behavior relevant to autism. Mice were monitored in tasks designed to assess social interaction, spatial learning and memory, and motor behavior. Portions of this data were later replicated to determine the phenotype of heterozygous mice. Deficits in social behavior were detected in En2 -/- mice in both replication datasets at two key points in maturation. During the juvenile period, En2-/- knockout mice exhibited dramatic reductions in play behavior compared to controls. In adulthood, the knockouts displayed deficient territorial aggression. Spatial learning and memory was assessed in the hidden-platform water maze and modified open-field with objects tests. En2-/- mice displayed deficits in both tasks. Analysis of motor performance revealed no difference in locomotor activity in an open-field. However, En2-/- mice displayed subtle disruptions in the development of some postnatal reflexes and deficient performance in a coordination task. To determine whether neurochemical changes were associated with these behavioral phenotypes, monoamine levels in specific brain regions were assessed in two replications. A two-fold, cerebellar-specific increase in serotonin and its metabolite was observed in the knockout. Interestingly, the serotonin pathway has consistently shown abnormalities in physiological, pharmacological, and genetic studies in autism. Importantly, heterozygous mice exhibited a wildtype phenotype when assessed for social behavior and neurochemistry. This indicates that one functional copy of En2-/- is enough to rescue the knockout phenotype. We conclude that En2 -/- mice display behavioral and neurochemical changes relevant to ASD, coupled with the genetic and neuropathological similarities. Therefore, these mice may be useful as an animal model of autism.