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Volume 16, Number 20,
Issue of October 15, 1996
pp. 6364-6373
Copyright ©1996 Society for Neuroscience
Impaired Cerebellar Synaptic Plasticity and Motor Performance in
Mice Lacking the mGluR4 Subtype of Metabotropic Glutamate
Receptor
Received June 14, 1996; revised July 24, 1996; accepted July 26, 1996.
Roman Pekhletski1,
Robert Gerlai2,
Linda S. Overstreet3,
Xi-Ping Huang1,
Nadia Agopyan2,
N. Traverse Slater3,
Wanda Abramow-Newerly2,
John C. Roder2, and
David R. Hampson1
1 Faculty of Pharmacy and Department of Pharmacology,
University of Toronto, and the MRC Group on Nerve Cells and Synapses,
Toronto, Ontario, Canada M5S 2S2, 2 Samuel Lunenfeld
Research Institute and the Department of Medical Genetics, University
of Toronto, Toronto, Ontario, Canada M5S 2S2, and
3 Department of Physiology and the Northwestern University
Institute for Neuroscience, Northwestern University Medical School,
Chicago, Illinois 60611
The application of the glutamate analog
L-2-amino-4-phosphonobutyric acid (L-AP4) to
neurons produces a suppression of synaptic transmission. Although
L-AP4 is a selective ligand at a subset of metabotropic
glutamate receptors (mGluRs), the precise physiological role of the
L-AP4-activated mGluRs remains primarily unknown. To
provide a better understanding of the function of L-AP4
receptors, we have generated and studied knockout (KO) mice lacking the
mGluR4 subtype of mGluR that displays high affinity for
L-AP4. The mGluR4 mutant mice displayed normal spontaneous
motor activity and were unimpaired on the bar cross test, indicating
that disruption of the mGluR4 gene did not cause gross motor
abnormalities, impairments of novelty-induced exploratory behaviors, or
alterations in fine motor coordination. However, the mutant mice were
deficient on the rotating rod motor-learning test, suggesting that
mGluR4 KO mice may have an impaired ability to learn complex motor
tasks. Patch-clamp and extracellular field recordings from Purkinje
cells in cerebellar slices demonstrated that L-AP4 had no
effect on synaptic responses in the mutant mice, whereas in the
wild-type mice 100 µM L-AP4 produced a 23%
depression of synaptic responses with an EC50 of 2.5 µM. An analysis of presynaptic short-term synaptic
plasticity at the parallel fiber Purkinje cell synapse demonstrated
that paired-pulse facilitation and post-tetanic potentiation were
impaired in the mutant mice. In contrast, long-term depression (LTD)
was not impaired. These results indicate that an important function of
mGluR4 is to provide a presynaptic mechanism for maintaining synaptic
efficacy during repetitive activation. The data also suggest that the
presence of mGluR4 at the parallel fiberPurkinje cell synapse is
required for maintaining normal motor function.
Key words:
L-AP4;
parallel fiber;
post-tetanic
potentiation;
Purkinje cell;
synaptic transmission;
gene targeting
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