TY - JOUR
T1 - Expression of a protein kinase C inhibitor in purkinje cells blocks cerebellar LTD and adaptation of the vestibulo-ocular reflex
AU - De Zeeuw, Chris I.
AU - Hansel, Christian
AU - Bian, Feng
AU - Koekkoek, Sebastiaan K.E.
AU - Van Alphen, Adriaan M.
AU - Linden, David J.
AU - Oberdick, John
N1 - Funding Information:
The authors would like to thank M. M. Morpurgo, J. v.d. Burg, R. Hawkins, E. Goedknegt, E. Dalm, D. Gurfel and E. Bugharin for technical assistance; J. Parker-Thornburg for construction of the L7-PKCI transgenic mouse lines; S. Baader for statistical analysis of cerebellar morphology; W. Russo and L. Eastman for animal care; and C. Aizenman and K. Takahashi for useful discussion. This research was supported by the Life Sciences Foundation (SLW; number 805–33.310-p; C.I.D.Z.), which is subsidized by the Netherlands Organization for Scientific Research (NWO); by a NWO project grant (number 903–68–361; C.I.D.Z.); by PHS MH51106, the Develbiss Fund, the McKnight Foundation, and the National Alliance for Research on Schizophrenia and Depression (D. J. L.); by the Deutsche Forschungsgemeinschaft (C. H.); and by NIH 1RO1NS33114 and NSF IBN-9309611 (J. O.).
PY - 1998/3
Y1 - 1998/3
N2 - 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.
AB - 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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U2 - 10.1016/S0896-6273(00)80990-3
DO - 10.1016/S0896-6273(00)80990-3
M3 - Article
C2 - 9539124
AN - SCOPUS:0032031999
SN - 0896-6273
VL - 20
SP - 495
EP - 508
JO - Neuron
JF - Neuron
IS - 3
ER -