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UBC Theses and Dissertations

The systems neurobiology of autism spectrum disorders (ASD) : a histological and functional approach Cairns, James Maxwell


Objective: To explore the relationship between cerebellar pathology and changes in neuronal activity in mouse models of autism-like phenotypes. Methods: We used the rotarod test as a measure of sensorimotor function in our mice and as a means to trigger neuronal activation. Following behavioural testing we obtained brain tissue from our ASD-like mouse models and used histology and microscopy to examine the expression of cFos (a reporter of neuronal activity) and several other structural and functional markers to evaluate cerebellar pathology. Finally, we looked at differences in the morphology, distribution and number of cerebellar glia in our ASD-like mouse models to determine if reactive gliosis contributes to further cerebellar pathology in adult mice. Results: Compared to wildtype littermates, Lc/+ mutant mice performed significantly worse on the rotarod assay of sensorimotor function (p<0.0001). In addition, Lc/+ mutants have significantly increased neuronal activity in the cerebellum and cortex at rest and following cerebellar rotarod activation as compared to wildtype littermates (p<0.05 for each group). Lurcher chimeras with the severest cerebellar pathology have increased neuronal activity in the GCL and CN neurons, but decreased neural activity in inhibitory PCs and they have increased numbers of activated microglia and Bergmann glia in the cerebellar cortex. Fmr1 KO mice have a slight decrease in PC numbers as compared to Fmr1 wildtypes (p=0.0862 n.s) with alterations in neuronal activity at rest in the cerebellar GCL and cortex. Conclusion: Variable cerebellar pathology seen in human cases of autism and in ASD-like mouse models in the form of neuron loss, microgliosis and astrogliosis leads to changes in excitatory and inhibitory activity in surviving cerebellar neurons. Structural and functional changes documented in Lc/+ mutants, chimeras and Fmr1 KO mice revealed neuroanatomical abnormalities and functional changes in cerebellar neural circuits which may lead to a better understanding of the neurobiological changes occurring in the cerebellum that contribute to ASD-like phenotypes. By identifying cerebellar neurons and glia that are involved in pathological processes in mouse models of neurodevelopmental disorders, it is hoped that these results will provide fresh insights into neurobiological changes underlying ASD-like phenotypes.

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