Long-term depression-inductive stimulation causes long-term potentiation in mouse Purkinje cells with a mutant thyroid hormone receptor.
Ayane NinomiyaIzuki AmanoMichifumi KokuboYusuke TakatsuruSumiyasu IshiiHirokazu HiraiNobutake HosoiNoriyuki KoibuchiPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
Thyroid hormones (THs) regulate gene expression by binding to nuclear TH receptors (TRs) in the cell. THs are indispensable for brain development. However, we have little knowledge about how congenital hypothyroidism in neurons affects functions of the central nervous system in adulthood. Here, we report specific TH effects on functional development of the cerebellum by using transgenic mice overexpressing a dominant-negative TR (Mf-1) specifically in cerebellar Purkinje cells (PCs). Adult Mf-1 mice displayed impairments in motor coordination and motor learning. Surprisingly, long-term depression (LTD)-inductive stimulation caused long-term potentiation (LTP) at parallel fiber (PF)-PC synapses in adult Mf-1 mice, although there was no abnormality in morphology or basal properties of PF-PC synapses. The LTP phenotype was turned to LTD in Mf-1 mice when the inductive stimulation was applied in an extracellular high-Ca<sup>2+</sup> condition. Confocal calcium imaging revealed that dendritic Ca<sup>2+</sup> elevation evoked by LTD-inductive stimulation is significantly reduced in Mf-1 PCs but not by PC depolarization only. Single PC messenger RNA quantitative analysis showed reduced expression of SERCA2 and IP<sub>3</sub> receptor type 1 in Mf-1 PCs, which are essential for mGluR1-mediated internal calcium release from endoplasmic reticulum in cerebellar PCs. These abnormal changes were not observed in adult-onset PC-specific TH deficiency mice created by adeno-associated virus vectors. Thus, we propose the importance of TH action during neural development in establishing proper cerebellar function in adulthood, independent of its morphology. The present study gives insight into the cellular and molecular mechanisms underlying congenital hypothyroidism-induced dysfunctions of central nervous system and cerebellum.
Keyphrases
- gene expression
- high fat diet induced
- induced apoptosis
- depressive symptoms
- endoplasmic reticulum
- healthcare
- cell cycle arrest
- single cell
- high resolution
- dna methylation
- type diabetes
- metabolic syndrome
- spinal cord
- skeletal muscle
- multiple sclerosis
- cerebrospinal fluid
- binding protein
- spinal cord injury
- sleep quality
- endoplasmic reticulum stress
- insulin resistance
- diabetic rats
- resting state
- oxidative stress
- pi k akt
- long non coding rna