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The Journal of Neuroscience, August 1, 2001, 21(15):5813-5823
Expression of Protein Kinase C Inhibitor Blocks Cerebellar Long-Term Depression without Affecting Purkinje Cell Excitability in Alert Mice
Jeroen Goossens1, 2, Hervé Daniel3, Armelle Rancillac3, Johannes van der Steen1, John Oberdick4, Francis Crépel3, Christiaan I. De Zeeuw5, and Maarten A. Frens1 1 Department of Physiology, Neuroscience Institute, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands, 2 Department of Medical Physics and Biophysics, University of Nijmegen, 6500 HB Nijmegen, The Netherlands, 3 Laboratory of Neurobiology, Institute of Neuroscience, University of Paris IV, 75252 Paris, France, 4 Department of Cell Biology, Ohio State University, Columbus, Ohio 43210, and 5 Department of Anatomy, Neuroscience Institute, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands
A longstanding but still controversial hypothesis is that long-term depression (LTD) of parallel fiber-Purkinje cell synapses in the cerebellum embodies part of the neuronal information storage required for associative motor learning. Transgenic mice in which LTD is blocked by Purkinje cell-specific inhibition of protein kinase C (PKC) (L7-PKCI mutants) do indeed show impaired adaptation of their vestibulo-ocular reflex, whereas the dynamics of their eye movement performance are unaffected. However, because L7-PKCI mutants have a persistent multiple climbing fiber innervation at least until 35 d of age and because the baseline discharge of the Purkinje cells in the L7-PKCI mutants is unknown, factors other than a blockage of LTD induction itself may underlie their impaired motor learning. We therefore investigated the spontaneous discharge of Purkinje cells in alert adult L7-PKCI mice as well as their multiple climbing fiber innervation beyond the age of 3 months. We found that the simple spike and complex spike-firing properties (such as mean firing rate, interspike interval, and spike count variability), oscillations, and climbing fiber pause in the L7-PKCI mutants were indistinguishable from those in their wild-type littermates. In addition, we found that multiple climbing fiber innervation does not occur in cerebellar slices obtained from 3- to 6-month-old mutants. These data indicate (1) that neither PKC inhibition nor the subsequent blockage of LTD induction disturbs the spontaneous discharge of Purkinje cells in alert mice, (2) that Purkinje cell-specific inhibition of PKC detains rather than prevents the developmental conversion from multiple to mono-innervation of Purkinje cells by climbing fibers, and (3) that as a consequence the impaired motor learning as observed in older adult L7-PKCI mutants cannot be attributable either to a disturbance in the baseline simple spike and complex spike activities of their Purkinje cells or to a persistent multiple climbing fiber innervation. We conclude that cerebellar LTD is probably one of the major mechanisms underlying motor learning, but that deficits in LTD induction and motor learning as observed in the L7-PKCI mutants may only be reflected in differences of the Purkinje cell signals during and/or directly after training.
Key words: heterosynaptic plasticity; motor learning; multiple climbing fiber innervation; cerebellar and vestibular nuclei; genetic manipulation; phosphorylation
Copyright © 2001 Society for Neuroscience 0270-6474/01/21155813-11$05.00/0
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