Altered Cerebellar Development in Nuclear Receptor TAK1/TR4 Null Mice Is Associated with Deficits in GLAST Glia, Alterations in Social Behavior, Motor Learning, Startle Reactivity, and Microglia.

Autor: Yong-Sik Kim, Harry, G. Jean, Hong Soon Kang, Goulding, David, Wine, Rob N., Kissling, Grace E., Liao, Grace, Jetten, Anton M.
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Zdroj: Cerebellum; Sep2010, Vol. 9 Issue 3, p310-323, 14p, 6 Color Photographs, 1 Black and White Photograph, 4 Graphs
Abstrakt: Previously, deficiency in the expression of the nuclear orphan receptor TAK1 was found to be associated with delayed cerebellar granule cell migration and Purkinje cell maturation with a permanent deficit in foliation of lobules VI-VII, suggesting a role for TAK1 in cerebellum development. In this study, we confirm that TAK1-deficient (TAK1) mice have a smaller cerebellum and exhibit a disruption of lobules VI-VII. We extended these studies and show that at postnatal day 7, TAK1 mice exhibit a delay in monolayer maturation of dysmorphic calbindin 28K-positive Purkinje cells. The astrocyte-specific glutamate transporter (GLAST) was expressed within Bergmann fibers and internal granule cell layer at significantly lower levels in the cerebellum of TAK1 mice. At PND21, Golgi-positive Purkinje cells in TAK1 mice displayed a smaller soma (18%) and shorter distance to first branch point (35%). Neuronal death was not observed in TAK1 mice at PND21; however, activated microglia were present in the cerebellum, suggestive of earlier cell death. These structural deficits in the cerebellum were not sufficient to alter motor strength, coordination, or activity levels; however, deficits in acoustic startle response, prepulse startle inhibition, and social interactions were observed. Reactions to a novel environment were inhibited in a light/dark chamber, open-field, and home-cage running wheel. TAK1 mice displayed a plateau in performance on the running wheel, suggesting a deficit in learning to coordinate performance on a motor task. These data indicate that TAK1 is an important transcriptional modulator of cerebellar development and neurodevelopmentally regulated behavior. [ABSTRACT FROM AUTHOR]
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