Aberrant cerebellar development in mice lacking dual oxidase maturation factors.

Aberrant cerebellar development in mice lacking dual oxidase maturation factors.

Thyroid. 2016 Feb 25;

Authors: Amano I, Takatsuru Y, Toya S, Haijima A, Iwasaki T, Grasberger H, Refetoff S, Koibuchi N

Abstract
BACKGROUND: Thyroid hormone (TH) plays a key role in the developing brain including the cerebellum. TH deficiency induces organizational changes of the cerebellum, causing cerebellar ataxia. However, the mechanisms causing these abnormalities are poorly understood. Various animal models have been used to study the mechanism. Lacking dual oxidase (DUOX) and its maturation factor (DUOXA) are major inducers of congenital hypothyroidism. Thus, we examined the organizational changes of the cerebellum using knockout mice of Duoxa gene (Duoxa-/-).
METHODS: We analyzed the morphological, behavioral, and electrophysiological changes in wild-type (Wt) and Duoxa deficient (Duoxa-/-) mice from postnatal day (P) 10 to P30. To detect the changes in the expression levels of presynaptic proteins, Western blot analysis was performed.
RESULTS: The proliferation and migration of granule cells was delayed after P15 in Duoxa-/- mice. However, these changes disappeared by P25. Although the cerebellar structure of Duoxa-/- mice was not significantly different from that of Wt mice at P25, motor coordination was impaired. We also found that the amplitude of paired-pulse facilitation at parallel fiber-Purkinje cell synapses decreased in Duoxa-/- mice, particularly at P15. There were no differences among expression levels of presynaptic proteins regulating neurotransmitter release at P25.
CONCLUSIONS: Our results indicate that the anatomical catch-up growth of the cerebellum did not normalize its function because of the disturbance of neuronal circuits by the combined effect of hypothyroidism and functional disruption of Duox/Duoxa complex.

PMID: 26914863 [PubMed - as supplied by publisher]

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