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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

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Abstract

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.

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Abbreviations

BrdU:

Bromodeoxyuridine

CAPS2:

Ca2+-dependent activator protein for secretion 2

DAB:

3,3′-Diaminobenzidine

DNER:

Delta/notch-like epidermal growth factor repeat

EGL:

External granular layer

GLAST:

L-glutamate/L-aspartate transporter

IGL:

Internal granular layer

MZ:

Marginal zone

ML:

Molecular layer

NMDA:

N-methyl-d-aspartic acid

PND:

Postnatal day

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Acknowledgements

The authors thank Dr. Randy Thresher, UNC/Chapel Hill, NC for generating TAK1−/− mice; Ms. Laura M. Degraff for technical assistance; Dr. Fu Du for the Golgi staining, and Drs. Gordon Flake (NIEHS) and Robert Berman (University of California/Davis) for comments. This research was supported by the Division of Intramural Research at the National Institute of Environmental Health Sciences, NIH (Z01-ES-101586; Z01-ES-021164).

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  1. Yong-Sik Kim

    Present address: Department Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

Authors and Affiliations

  1. Laboratory of Respiratory Biology, Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA

    Yong-Sik Kim, Hong Soon Kang, Grace Liao & Anton M. Jetten

  2. Laboratory of Molecular Toxicology, Division of Intramural Research, National Institute of Environmental Health Sciences National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA

    G. Jean Harry & Rob N. Wine

  3. Comparative Medicine Branch, Division of Intramural Research, National Institute of Environmental Health Sciences National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA

    David Goulding

  4. Biostatistics Branch, Division of Intramural Research, National Institute of Environmental Health Sciences National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA

    Grace E. Kissling

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  1. Yong-Sik Kim
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Correspondence to G. Jean Harry or Anton M. Jetten.

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Kim, YS., Harry, G.J., Kang, H.S. et al. 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. Cerebellum 9, 310–323 (2010). https://doi.org/10.1007/s12311-010-0163-z

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