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

Academic Article

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. © 2010 US Government.
  • Published In

  • Cerebellum  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 9694834
  • Author List

  • Kim YS; Harry GJ; Kang HS; Goulding D; Wine RN; Kissling GE; Liao G; Jetten AM
  • Start Page

  • 310
  • End Page

  • 323
  • Volume

  • 9
  • Issue

  • 3