Abnormal cerebellar cytoarchitecture and impaired inhibitory signaling in adult mice lacking TR4 orphan nuclear receptor.
Since testicular orphan nuclear receptor 4 (TR4) was cloned, its physiological functions remain largely unknown. In this study, the TR4 knockout (TR4(-/-)) mouse model was used to investigate the role of TR4 in the adult cerebellum. Behaviorally, these null mice exhibit unsteady gait, as well as involuntary postural and kinetic movements, indicating a disturbance of cerebellar function. In the TR4(-/-) brain, cerebellar restricted hypoplasia is severe and cerebellar vermal lobules VI and VII are underdeveloped, while no structural alterations in the cerebral cortex are observed. Histological analysis of the TR4(-/-) cerebellar cortex reveals reductions in granule cell density, as well as a decreased number of parallel fiber boutons that are enlarged in size. Further analyses reveal that the levels of GABA and GAD are decreased in both Purkinje cells and interneurons of the TR4(-/-) cerebellum, suggesting that the inhibitory circuits signaling within and from the cerebellum may be perturbed. In addition, in the TR4(-/-) cerebellum, immunoreactivity of GluR2/3 was reduced in Purkinje cells, but increased in the deep cerebellar nuclei. Together, these results suggest that the behavioral phenotype of TR4(-/-) mice may result from disrupted inhibitory pathways in the cerebellum. No progressive atrophy was observed at various adult stages in the TR4(-/-) brain, therefore the disturbances most likely originate from a failure to establish proper connections between principal neurons in the cerebellum during development.
Chen
Yei-Tsung
YT
Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Collins
Loretta L
LL
Uno
Hideo
H
Chou
Samuel M
SM
Meshul
Charles K
CK
Chang
Shu-Shi
SS
Chang
Chawnshang
C
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002526:Cerebellar Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002531:Cerebellum / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009043:Motor Activity / Q000235:genetics; D011987:Receptors, Steroid / Q000172:deficiency*; D011988:Receptors, Thyroid Hormone / Q000172:deficiency*; D015398:Signal Transduction / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C092882:Nr2c2 protein, rat; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase
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