The weaver GIRK2 mutation leads to decreased levels of serum thyroid hormone: characterization of the effect on midbrain dopaminergic neuron survival.
The selective neurodegenerative changes occurring in the weaver mutant cerebellum and midbrain are linked to a point mutation in an inward rectifying potassium channel (GIRK2). However, given that GIRK2 is widely expressed in the CNS, it is not understood why this mutation only leads to neuroanatomically selective and developmentally specific neuronal cell death. Here we show that the phenotype of the weaver mutant mouse includes hypothyroidism, which is associated with delays in somatic development and decreased expression of striatal transforming growth factor alpha (TGF-alpha). Since thyroid hormone has major effects on brain development, further studies were performed to address whether some of pathological changes detected the weaver mutant mouse are due to the reduced thyroid hormone levels. We observed that daily thyroid hormone replacement was able to stimulate somatic growth and restore TGF-alpha expression to wild-type levels, indicating that while these mice are responsive to thyroid hormone they possibly have a defect in the ability to regulate its release at the level of the hypothalamic pituitary axis. However, when we assessed whether thyroid hormone replacement could rescue midbrain dopaminergic neurons we found that this treatment accelerated rather than attenuated neurodegeneration. We did not observe that thyroid hormone was able to directly regulate expression of GIRK2 mRNA levels in the midbrain and therefore, speculate that the mechanism by which thyroid hormone accelerates midbrain dopaminergic neurodegeneration is by enhancing the maturation of the striatonigral inputs. In summary, we detected reduced levels of serum thyroid hormone in the weaver mutant mouse, which appears to be responsible for delays in somatic growth and the onset of neurodegenerative changes in the midbrain.
Blum
M
M
Fishberg Research Center for Neurobiology, Mt. Sinai School of Medicine, New York, New York 10029, USA.
Weickert
C
C
Carrasco
E
E
D000818:Animals; D002470:Cell Survival; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D005786:Gene Expression Regulation; D006579:Heterozygote; D007037:Hypothyroidism / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008636:Mesencephalon / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008818:Mice, Neurologic Mutants; D009474:Neurons / Q000473:pathology* / Q000502:physiology*; D010641:Phenotype; D017354:Point Mutation; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying; D013963:Thyroid Hormones / Q000097:blood; D013974:Thyroxine / Q000627:therapeutic use*; D014158:Transcription, Genetic; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D013963:Thyroid Hormones; D016211:Transforming Growth Factor alpha; D014446:Tyrosine 3-Monooxygenase; D013974:Thyroxine; D004298:Dopamine