Differential development of central dopaminergic and serotonergic systems in BALB/c and C57BL/6J mice.

Although the etiology of autism is unclear, disruptions of the dopaminergic and serotonergic systems have been associated with the disorder. Based on behavioral differences observed in the BALB/c strain of mice in comparison to other strains, notably, C57BL/6J mice, it has been suggested that the BALB/c strain may serve as an animal model of autism. However, to date, most work investigating neural and behavioral abnormalities in this strain has been performed in adult animals. Therefore, the present study was conducted to examine the development of the central dopaminergic and serotonergic systems of BALB/c mice as compared to C57BL/6J mice. Levels of dopamine, serotonin, and their metabolites in several different brain regions and at three ages during development were measured. Alterations in both monoaminergic systems associated with age and strain were detected across brain regions indicating that there are neurochemical differences between these strains early in life. However, despite these differences in the development of brain monoaminergic systems, it remains difficult to declare this strain as a valid model of autism.

En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder.

Autism spectrum disorder (ASD) is a prevalent and inheritable neurodevelopmental disorder. Recent human genetic studies are consistent with the homeobox transcription factor, ENGRAILED 2 (EN2), being an ASD susceptibility gene. En2 knockout mice (En2(-/-)) display subtle cerebellar neuropathological changes similar to what has been observed in the ASD brain. To investigate whether En2(-/-) mice displayed abnormal behavior relevant to ASD, they were monitored in tasks designed to assess social maturation as well as learning and memory. Deficits in social behavior were detected in En2(-/-) mice across maturation that included decreased play, reduced social sniffing and allogrooming, and less aggressive behavior. Deficits in two spatial learning and memory tasks were also observed. Because locomotor activity was a component of many of the behavioral tasks, this was measured at various stages of development. Locomotor activity was not compromised in the knockout. However, a more thorough analysis of motor behavior in En2(-/-) mice revealed deficits in specific motor tasks. To determine whether neurochemical changes were associated with these behavioral phenotypes, monoamine levels in specific brain regions were assessed. A cerebellar-specific increase in serotonin and its metabolite was observed. Interestingly, several reports have suggested that the serotonin pathway is affected in ASD. We conclude that En2(-/-) mice display behavioral and neurochemical changes, in addition to genetic and neuropathological changes, relevant to ASD. Therefore, these mice may be useful as an animal model of autism.