Abstract
BackgroundPurkinje cells play a central role in establishing the cerebellar circuit. Accordingly, disrupting Purkinje cell development impairs cerebellar morphogenesis and motor function. In the Car8wdl mouse model of hereditary ataxia, severe motor deficits arise despite the cerebellum overcoming initial defects in size and morphology.MethodsTo resolve how this compensation occurs, we asked how the loss of carbonic anhydrase 8 (CAR8), a regulator of IP3R1 Ca2+ signaling in Purkinje cells, alters cerebellar development in Car8wdl mice. Using a combination of histological, physiological, and behavioral analyses, we determined the extent to which the loss of CAR8 affects cerebellar anatomy, neuronal firing, and motor coordination during development.ResultsOur results reveal that granule cell proliferation is reduced in early postnatal mutants, although by the third postnatal week there is enhanced and prolonged proliferation, plus an upregulation of Sox2 expression in the inner EGL. Modified circuit patterning of Purkinje cells and Bergmann glia accompany these granule cell adjustments. We also find that although anatomy eventually normalizes, the abnormal activity of neurons and muscles persists.ConclusionsOur data show that losing CAR8 only transiently restricts cerebellar growth, but permanently damages its function. These data support two current hypotheses about cerebellar development and disease: (1) Sox2 expression may be upregulated at sites of injury and contribute to the rescue of cerebellar structure and (2) transient delays to developmental processes may precede permanent motor dysfunction. Furthermore, we characterize waddles mutant mouse morphology and behavior during development and propose a Sox2-positive, cell-mediated role for rescue in a mouse model of human motor diseases.
Highlights
The cerebellum controls motor coordination, motor learning, posture, and balance
Transient anatomical alterations precede motor dysfunction carbonic anhydrase 8 (CAR8) protein is heavily expressed in Purkinje cells (Fig. 1a-f )
The morphology of the adult Car8wdl cerebellum is ostensibly normal, we found that the molecular layer (ML) is significantly thinner in Car8wdl at P30 [30]
Summary
The cerebellum controls motor coordination, motor learning, posture, and balance. damage to its circuits causes a number of motor disorders, such as ataxia, dystonia, and tremor [1,2,3,4,5,6,7]. The functional architecture of the cerebellum is established through multiple morphogenetic, patterning, and remodeling processes [14] These processes include lobule (2019) 14:6 formation, zonal patterning of zebra-like striped compartments, and afferent fiber synaptogenesis. It has been challenging to parse out how developmental defects impact the onset of motor dysfunction in animal models of movement disease. Major reasons for this challenge are that the affected Purkinje cells can degenerate, undergo cell death, or even look normal but function poorly due to a compromised circuit. In the Car8wdl mouse model of hereditary ataxia, severe motor deficits arise despite the cerebellum overcoming initial defects in size and morphology
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