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      Contribution of Thyrotropin-Releasing Hormone to Cerebellar Long-Term Depression and Motor Learning

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          Thyrotropin-releasing hormone (TRH) regulates various physiological activities through activation of receptors expressed in a broad range of cells in the central nervous system. The cerebellum expresses TRH receptors in granule cells and molecular layer interneurons. However, the function of TRH in the cerebellum remains to be clarified. Here, using TRH knockout (KO) mice we studied the role of TRH in the cerebellum. Immunohistochemistry showed no gross morphological differences between KO mice and wild-type (WT) littermates in the cerebellum. In the rotarod test, the initial performance of KO mice was comparable to that of WT littermates, but the learning speed of KO mice was significantly lower than that of WT littermates, suggesting impaired motor learning. The motor learning deficit in KO mice was rescued by intraperitoneal injection of TRH. Electrophysiology revealed absence of long-term depression (LTD) at parallel fiber-Purkinje cell synapses in KO mice, which was rescued by bath-application of TRH. TRH was shown to increase cyclic guanosine monophosphate (cGMP) content in the cerebellum. Since nitric oxide (NO) stimulates cGMP synthesis in the cerebellum, we examined whether NO-cGMP pathway was involved in TRH-mediated LTD rescue in KO mice. Pharmacological blockade of NO synthase and subsequent cGMP production prevented TRH-induced LTD expression in KO mice, whereas increase in cGMP signal in Purkinje cells by 8-bromoguanosine cyclic 3’,5’-monophosphate, a membrane-permeable cGMP analog, restored LTD without TRH application. These results suggest that TRH is involved in cerebellar LTD presumably by upregulating the basal cGMP level in Purkinje cells, and, consequently, in motor learning.

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          Cerebellar long-term depression: characterization, signal transduction, and functional roles.

           Yoichi Ito (2001)
          Cerebellar Purkinje cells exhibit a unique type of synaptic plasticity, namely, long-term depression (LTD). When two inputs to a Purkinje cell, one from a climbing fiber and the other from a set of granule cell axons, are repeatedly associated, the input efficacy of the granule cell axons in exciting the Purkinje cell is persistently depressed. Section I of this review briefly describes the history of research around LTD, and section II specifies physiological characteristics of LTD. Sections III and IV then review the massive data accumulated during the past two decades, which have revealed complex networks of signal transduction underlying LTD. Section III deals with a variety of first messengers, receptors, ion channels, transporters, G proteins, and phospholipases. Section IV covers second messengers, protein kinases, phosphatases and other elements, eventually leading to inactivation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolone-propionate-selective glutamate receptors that mediate granule cell-to-Purkinje cell transmission. Section V defines roles of LTD in the light of the microcomplex concept of the cerebellum as functionally eliminating those synaptic connections associated with errors during repeated exercises, while preserving other connections leading to the successful execution of movements. Section VI examines the validity of this microcomplex concept based on the data collected from recent numerous studies of various forms of motor learning in ocular reflexes, eye-blink conditioning, posture, locomotion, and hand/arm movements. Section VII emphasizes the importance of integrating studies on LTD and learning and raises future possibilities of extending cerebellar research to reveal memory mechanisms of implicit learning in general.
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            Cerebellar involvement in executive control.

            The cerebellum has long been considered to be mainly involved in motor function. In the last 20 years, evidence from neuroimaging studies and from investigations of patients with cerebellar lesions has shown that the cerebellum plays a role in a range of cognitive functions. While cerebellar contributions have been shown for learning and memory, the cerebellum has also been linked to higher order cognitive control processes frequently referred to as executive functions. Although it is widely accepted that the cerebellum contributes to cognitive processing, the nature of cerebellar involvement is not well understood. The present paper focuses on the role of the cerebellum in executive processing, reviewing findings derived from neuroimaging studies or from studies investigating deficits related to cerebellar dysfunction. As executive functions cannot be considered as a unitary concept, special emphasis is put on cerebellar contributions to different aspects of executive control such as working memory, multitasking or inhibition. Referring to models derived from motor control, possible mechanisms of cerebellar involvement in executive processing are discussed. Finally, methodological problems in assessing executive deficits in general and in assessing the cerebellar contribution to executive processing in particular are addressed.
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              Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression.

              Cerebellar long-term depression (LTD) is a model of synaptic memory that requires protein kinase C (PKC) activation and is expressed as a reduction in the number of postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. LTD was absent in cultured cerebellar Purkinje cells from mutant mice lacking the AMPA receptor GluR2 subunit and could be rescued by transient transfection with the wild-type GluR2 subunit. Transfection with a point mutant that eliminated PKC phosphorylation of Ser880 in the carboxy-terminal PDZ ligand of GluR2 failed to restore LTD. In contrast, transfection with a point mutant that mimicked phosphorylation at Ser880 occluded subsequent LTD. Thus, PKC phosphorylation of GluR2 Ser880 is a critical event in the induction of cerebellar LTD.

                Author and article information

                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                12 December 2018
                : 12
                1Department of Neurophysiology and Neural Repair, Gunma University Graduate School of Medicine , Maebashi, Japan
                2Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine , Maebashi, Japan
                3Research Program for Neural Signalling, Division of Endocrinology, Metabolism and Signal Research, Gunma University Initiative for Advanced Research , Maebashi, Japan
                Author notes

                Edited by: Jing-Ning Zhu, Nanjing University, China

                Reviewed by: Maria Concetta Miniaci, University of Naples Federico II, Italy; Eriola Hoxha, Università degli Studi di Torino, Italy

                *Correspondence: Hirokazu Hirai, hirai@ 123456gunma-u.ac.jp
                Copyright © 2018 Watanave, Matsuzaki, Nakajima, Ozawa, Yamada and Hirai.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 8, Tables: 1, Equations: 0, References: 46, Pages: 12, Words: 0
                Funded by: Japan Society for the Promotion of Science 10.13039/501100001691
                Award ID: 15H04254
                Award ID: 16K15477
                Award ID: 18H02521
                Award ID: 17K14929
                Funded by: Ministry of Health, Labour and Welfare 10.13039/501100003478
                Original Research


                thyrotropin-releasing hormone, motor learning, cerebellum, ltd, no


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