Long-term Depression-inductive Stimulation Causes Long-term Potentiation in Mouse Purkinje Cells with a Mutant Thyroid Hormone Receptor

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2022 Nov 2

PMID 36322758

Authors

Ayane Ninomiya

Izuki Amano

Michifumi Kokubo

Yusuke Takatsuru

Sumiyasu Ishii

Hirokazu Hirai

Nobutake Hosoi

Noriyuki Koibuchi

Affiliations

Soon will be listed here.

Abstract

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 condition. Confocal calcium imaging revealed that dendritic Ca 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 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.

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References

Safo P, Cravatt B, Regehr W . Retrograde endocannabinoid signaling in the cerebellar cortex. Cerebellum. 2006; 5(2):134-45. DOI: 10.1080/14734220600791477. View

Yu L, Iwasaki T, Xu M, Lesmana R, Xiong Y, Shimokawa N . Aberrant cerebellar development of transgenic mice expressing dominant-negative thyroid hormone receptor in cerebellar Purkinje cells. Endocrinology. 2015; 156(4):1565-76. DOI: 10.1210/en.2014-1079. View

Yuzaki M . Cerebellar LTD vs. motor learning-lessons learned from studying GluD2. Neural Netw. 2012; 47:36-41. DOI: 10.1016/j.neunet.2012.07.001. View

Hansel C, de Jeu M, Belmeguenai A, Houtman S, Buitendijk G, Andreev D . alphaCaMKII Is essential for cerebellar LTD and motor learning. Neuron. 2006; 51(6):835-43. DOI: 10.1016/j.neuron.2006.08.013. View

Mata A, Sepulveda M . Calcium pumps in the central nervous system. Brain Res Brain Res Rev. 2005; 49(2):398-405. DOI: 10.1016/j.brainresrev.2004.11.004. View

Kano M, Hashimoto K, Tabata T . Type-1 metabotropic glutamate receptor in cerebellar Purkinje cells: a key molecule responsible for long-term depression, endocannabinoid signalling and synapse elimination. Philos Trans R Soc Lond B Biol Sci. 2008; 363(1500):2173-86. PMC: 2610189. DOI: 10.1098/rstb.2008.2270. View

Gao Z, van Beugen B, De Zeeuw C . Distributed synergistic plasticity and cerebellar learning. Nat Rev Neurosci. 2012; 13(9):619-35. DOI: 10.1038/nrn3312. View

Ito M . Cerebellar long-term depression: characterization, signal transduction, and functional roles. Physiol Rev. 2001; 81(3):1143-95. DOI: 10.1152/physrev.2001.81.3.1143. View

Fauquier T, Chatonnet F, Picou F, Richard S, Fossat N, Aguilera N . Purkinje cells and Bergmann glia are primary targets of the TRα1 thyroid hormone receptor during mouse cerebellum postnatal development. Development. 2013; 141(1):166-75. DOI: 10.1242/dev.103226. View

10.

Strait K, Zou L, OPPENHEIMER J . Beta 1 isoform-specific regulation of a triiodothyronine-induced gene during cerebellar development. Mol Endocrinol. 1992; 6(11):1874-80. DOI: 10.1210/mend.6.11.1282672. View

11.

van Woerden G, Hoebeek F, Gao Z, Nagaraja R, Hoogenraad C, Kushner S . betaCaMKII controls the direction of plasticity at parallel fiber-Purkinje cell synapses. Nat Neurosci. 2009; 12(7):823-5. DOI: 10.1038/nn.2329. View

12.

Chatonnet F, Guyot R, Benoit G, Flamant F . Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells. Proc Natl Acad Sci U S A. 2013; 110(8):E766-75. PMC: 3581916. DOI: 10.1073/pnas.1210626110. View

13.

Tanaka K, Khiroug L, Santamaria F, Doi T, Ogasawara H, Ellis-Davies G . Ca2+ requirements for cerebellar long-term synaptic depression: role for a postsynaptic leaky integrator. Neuron. 2007; 54(5):787-800. DOI: 10.1016/j.neuron.2007.05.014. View

14.

Sergaki M, Lopez-Ramos J, Stagkourakis S, Gruart A, Broberger C, Delgado-Garcia J . Compromised Survival of Cerebellar Molecular Layer Interneurons Lacking GDNF Receptors GFRα1 or RET Impairs Normal Cerebellar Motor Learning. Cell Rep. 2017; 19(10):1977-1986. PMC: 5469938. DOI: 10.1016/j.celrep.2017.05.030. View

15.

Talley E, Cribbs L, Lee J, Daud A, Perez-Reyes E, Bayliss D . Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci. 1999; 19(6):1895-911. PMC: 6782581. View

16.

Wulff P, Schonewille M, Renzi M, Viltono L, Sassoe-Pognetto M, Badura A . Synaptic inhibition of Purkinje cells mediates consolidation of vestibulo-cerebellar motor learning. Nat Neurosci. 2009; 12(8):1042-9. PMC: 2718327. DOI: 10.1038/nn.2348. View

17.

Isope P, Murphy T . Low threshold calcium currents in rat cerebellar Purkinje cell dendritic spines are mediated by T-type calcium channels. J Physiol. 2004; 562(Pt 1):257-69. PMC: 1665489. DOI: 10.1113/jphysiol.2004.074211. View

18.

Morte B, Gil-Ibanez P, Heuer H, Bernal J . Brain Gene Expression in Systemic Hypothyroidism and Mouse Models of MCT8 Deficiency: The Mct8-Oatp1c1-Dio2 Triad. Thyroid. 2020; 31(6):985-993. DOI: 10.1089/thy.2020.0649. View

19.

OPPENHEIMER J, Schwartz H . Molecular basis of thyroid hormone-dependent brain development. Endocr Rev. 1997; 18(4):462-75. DOI: 10.1210/edrv.18.4.0309. View

20.

Ishii S, Amano I, Koibuchi N . The Role of Thyroid Hormone in the Regulation of Cerebellar Development. Endocrinol Metab (Seoul). 2021; 36(4):703-716. PMC: 8419606. DOI: 10.3803/EnM.2021.1150. View