Global and Age-related Neuroanatomical Abnormalities in a Pax6-deficient Mouse Model of Aniridia Suggests a Role for Pax6 in Adult Structural Neuroplasticity

PAX6 encodes a highly conserved transcription factor necessary for normal development of the eyes and central nervous system. Heterozygous loss-of-function mutations in PAX6 cause the disorder aniridia in humans and the Small eye trait in mice. Aniridia is a congenital and progressive disorder known for ocular phenotypes; however, recently, consequences of PAX6 haploinsufficiency in the brains of aniridia patients have been identified. These findings span structural and functional abnormalities, including deficits in cognitive and sensory processing. Furthermore, some of these abnormalities are accelerated as aniridia patients age. Although some functional abnormalities may be explained by structural changes, variability of results remain, and the effects of PAX6 heterozygous loss-of-function mutations on neuroanatomy, particularly with regard to aging, have yet to be resolved. Our study used high-resolution magnetic resonance imaging (MRI) and histology to investigate structural consequences of such mutations in the adult brain of our aniridia mouse model, Small eye Neuherberg allele (Pax6), at two adult age groups. Using both MRI and histology enables a direct comparison with human studies, while providing higher resolution for detection of more subtle changes. We show volumetric changes in major brain regions of the the Pax6 mouse compared to wild-type including genotype- and age-related olfactory bulb differences, age-related cerebellum differences, and genotype-related eye differences. We also show alterations in thickness of major interhemispheric commissures, particularly those anteriorly located within the brain including the optic chiasm, corpus callosum, and anterior commissure. Together, these genotype and age related changes to brain volumes and structures suggest a global decrease in adult brain structural plasticity in our Pax6 mice.