Expression of a Protein Kinase C Inhibitor in Purkinje Cells Blocks Cerebellar LTD and Adaptation of the Vestibulo-Ocular Reflex
Cerebellar long-term depression (LTD) is a model system for neuronal information storage that has an absolute requirement for activation of protein kinase C (PKC). It has been claimed to underlie several forms of cerebellar motor learning. Previous studies using various knockout mice (mGluR1, GluRδ2...
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| Published in: | Neuron (Cambridge, Mass.) Vol. 20; no. 3; pp. 495 - 508 |
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| Main Authors: | , , , , , , |
| Format: | Journal Article |
| Language: | English |
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United States
Elsevier Inc
01-03-1998
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| Abstract | Cerebellar long-term depression (LTD) is a model system for neuronal information storage that has an absolute requirement for activation of protein kinase C (PKC). It has been claimed to underlie several forms of cerebellar motor learning. Previous studies using various knockout mice (mGluR1, GluRδ2, glial fibrillary acidic protein) have supported this claim; however, this work has suffered from the limitations that the knockout technique lacks anatomical specificity and that functional compensation can occur via similar gene family members. To overcome these limitations, a transgenic mouse (called L7-PKCI) has been produced in which the pseudosubstrate PKC inhibitor, PKC[19–31], was selectively expressed in Purkinje cells under the control of the pcp-2(L7) gene promoter. Cultured Purkinje cells prepared from heterozygous or homozygous L7-PKCI embryos showed a complete blockade of LTD induction. In addition, the compensatory eye movements of L7-PKCI mice were recorded during vestibular and visual stimulation. Whereas the absolute gain, phase, and latency values of the vestibulo-ocular reflex and optokinetic reflex of the L7-PKCI mice were normal, their ability to adapt their vestibulo-ocular reflex gain during visuo-vestibular training was absent. These data strongly support the hypothesis that activation of PKC in the Purkinje cell is necessary for cerebellar LTD induction, and that cerebellar LTD is required for a particular form of motor learning, adaptation of the vestibulo-ocular reflex. |
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| AbstractList | Cerebellar long-term depression (LTD) is a model system for neuronal information storage that has an absolute requirement for activation of protein kinase C (PKC). It has been claimed to underlie several forms of cerebellar motor learning. Previous studies using various knockout mice (mGluR1, GluR delta 2, glial fibrillary acidic protein) have supported this claim; however, this work has suffered from the limitations that the knockout technique lacks anatomical specificity and that functional compensation can occur via similar gene family members. To overcome these limitations, a transgenic mouse (called L7-PKCI) has been produced in which the pseudosubstrate PKC inhibitor, PKC, was selectively expressed in Purkinje cells under the control of the pcp-2(L7) gene promoter. Cultured Purkinje cells prepared from heterozygous or homozygous L7-PKCI embryos showed a complete blockade of LTD induction. In addition, the compensatory eye movements of L7-PKCI mice were recorded during vestibular and visual stimulation. Whereas the absolute gain, phase, and latency values of the vestibulo-ocular reflex and optokinetic reflex of the L7-PKCI mice were normal, their ability to adapt their vestibulo-ocular reflex gain during visuo-vestibular training was absent. These data strongly support the hypothesis that activation of PKC in the Purkinje cell is necessary for cerebellar LTD induction, and that cerebellar LTD is required for a particular form of motor learning, adaptation of the vestibulo-ocular reflex. Cerebellar long-term depression (LTD) is a model system for neuronal information storage that has an absolute requirement for activation of protein kinase C (PKC). It has been claimed to underlie several forms of cerebellar motor learning. Previous studies using various knockout mice (mGluR1, GluRdelta2, glial fibrillary acidic protein) have supported this claim; however, this work has suffered from the limitations that the knockout technique lacks anatomical specificity and that functional compensation can occur via similar gene family members. To overcome these limitations, a transgenic mouse (called L7-PKCI) has been produced in which the pseudosubstrate PKC inhibitor, PKC[19-31], was selectively expressed in Purkinje cells under the control of the pcp-2(L7) gene promoter. Cultured Purkinje cells prepared from heterozygous or homozygous L7-PKCI embryos showed a complete blockade of LTD induction. In addition, the compensatory eye movements of L7-PKCI mice were recorded during vestibular and visual stimulation. Whereas the absolute gain, phase, and latency values of the vestibulo-ocular reflex and optokinetic reflex of the L7-PKCI mice were normal, their ability to adapt their vestibulo-ocular reflex gain during visuo-vestibular training was absent. These data strongly support the hypothesis that activation of PKC in the Purkinje cell is necessary for cerebellar LTD induction, and that cerebellar LTD is required for a particular form of motor learning, adaptation of the vestibulo-ocular reflex. Cerebellar long-term depression (LTD) is a model system for neuronal information storage that has an absolute requirement for activation of protein kinase C (PKC). It has been claimed to underlie several forms of cerebellar motor learning. Previous studies using various knockout mice (mGluR1, GluRδ2, glial fibrillary acidic protein) have supported this claim; however, this work has suffered from the limitations that the knockout technique lacks anatomical specificity and that functional compensation can occur via similar gene family members. To overcome these limitations, a transgenic mouse (called L7-PKCI) has been produced in which the pseudosubstrate PKC inhibitor, PKC[19–31], was selectively expressed in Purkinje cells under the control of the pcp-2(L7) gene promoter. Cultured Purkinje cells prepared from heterozygous or homozygous L7-PKCI embryos showed a complete blockade of LTD induction. In addition, the compensatory eye movements of L7-PKCI mice were recorded during vestibular and visual stimulation. Whereas the absolute gain, phase, and latency values of the vestibulo-ocular reflex and optokinetic reflex of the L7-PKCI mice were normal, their ability to adapt their vestibulo-ocular reflex gain during visuo-vestibular training was absent. These data strongly support the hypothesis that activation of PKC in the Purkinje cell is necessary for cerebellar LTD induction, and that cerebellar LTD is required for a particular form of motor learning, adaptation of the vestibulo-ocular reflex. |
| Author | De Zeeuw, Chris I. Koekkoek, Sebastiaan K.E. van Alphen, Adriaan M. Hansel, Christian Bian, Feng Linden, David J. Oberdick, John |
| Author_xml | – sequence: 1 givenname: Chris I. surname: De Zeeuw fullname: De Zeeuw, Chris I. organization: Department of Anatomy, Erasmus University Rotterdam, 3000 DR, Rotterdam, The Netherlands – sequence: 2 givenname: Christian surname: Hansel fullname: Hansel, Christian organization: Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA – sequence: 3 givenname: Feng surname: Bian fullname: Bian, Feng organization: Department of Cell Biology, Neurobiology and Anatomy/Neuroscience Division, and the Neurobiotechnology Center, The Ohio State University, Columbus, Ohio 43210, USA – sequence: 4 givenname: Sebastiaan K.E. surname: Koekkoek fullname: Koekkoek, Sebastiaan K.E. organization: Department of Anatomy, Erasmus University Rotterdam, 3000 DR, Rotterdam, The Netherlands – sequence: 5 givenname: Adriaan M. surname: van Alphen fullname: van Alphen, Adriaan M. organization: Department of Anatomy, Erasmus University Rotterdam, 3000 DR, Rotterdam, The Netherlands – sequence: 6 givenname: David J. surname: Linden fullname: Linden, David J. organization: Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA – sequence: 7 givenname: John surname: Oberdick fullname: Oberdick, John email: oberdick.1@osu.edu organization: Department of Cell Biology, Neurobiology and Anatomy/Neuroscience Division, and the Neurobiotechnology Center, The Ohio State University, Columbus, Ohio 43210, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/9539124$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Animals Cells, Cultured Electrophysiology Eye Movements - physiology Female Gene Expression Regulation, Developmental - genetics Long-Term Potentiation - physiology Male Mice Mice, Transgenic - physiology Microscopy, Electron Motor Neurons - physiology Protein Kinase C - antagonists & inhibitors Purkinje Cells - cytology Purkinje Cells - enzymology Purkinje Cells - ultrastructure Reflex, Vestibulo-Ocular - physiology Space life sciences Transgenes - genetics |
| Title | Expression of a Protein Kinase C Inhibitor in Purkinje Cells Blocks Cerebellar LTD and Adaptation of the Vestibulo-Ocular Reflex |
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