Repetitive behavior and increased activity in mice with Purkinje cell loss: a model for understanding the role of cerebellar pathology in autism.
Repetitive behaviors and hyperactivity are common features of developmental disorders, including autism. Neuropathology of the cerebellum is also a frequent occurrence in autism and other developmental disorders. Recent studies have indicated that cerebellar pathology may play a causal role in the generation of repetitive and hyperactive behaviors. In this study, we examined the relationship between cerebellar pathology and these behaviors in a mouse model of Purkinje cell loss. Specifically, we made aggregation chimeras between Lc/+ mutant embryos and +/+ embryos. Lc/+ mice lose 100% of their Purkinje cells postnatally due to a cell-intrinsic gain-of-function mutation. Through our histological examination, we demonstrated that Lc/+<-->+/+ chimeric mice have Purkinje cells ranging from zero to normal numbers. Our analysis of these chimeric cerebella confirmed previous studies on Purkinje cell lineage. The results of both open-field activity and hole-board exploration testing indicated negative relationships between Purkinje cell number and measures of activity and investigatory nose-poking. Additionally, in a progressive-ratio operant paradigm, we found that Lc/+ mice lever-pressed significantly less than +/+ controls, which led to significantly lower breakpoints in this group. In contrast, chimeric mice lever-pressed significantly more than controls and this repetitive lever-pressing behavior was significantly and negatively correlated with total Purkinje cell numbers. Although the performance of Lc/+ mice is probably related to their motor deficits, the significant relationships between Purkinje cell number and repetitive lever-pressing behavior as well as open-field activity measures provide support for a role of cerebellar pathology in generating repetitive behavior and increased activity in chimeric mice.
Martin
Loren A
LA
Department of Psychology, Azusa Pacific University, Azusa, CA 91702, USA. lamartin@apu.edu
Goldowitz
Dan
D
Mittleman
Guy
G
D000818:Animals; D001321:Autistic Disorder / Q000473:pathology / Q000503:physiopathology; D001522:Behavior, Animal / Q000502:physiology*; D002531:Cerebellum / Q000473:pathology*; D002648:Child; D002678:Chimera; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009043:Motor Activity / Q000502:physiology; D009483:Neuropsychological Tests; D011247:Pregnancy; D011689:Purkinje Cells / Q000473:pathology* / Q000502:physiology