Enhanced G protein-dependent modulation of excitatory synaptic transmission in the cerebellum of the Ca2+ channel-mutant mouse, tottering
Tottering , a mouse model for absence epilepsy and cerebellar ataxia, carries a mutation in the gene encoding class A (P/Q-type) Ca 2+ channels, the dominant exocytotic Ca 2+ channel at most synapses in the mammalian central nervous system. Comparing tottering to wild-type mice, we have studied glut...
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Published in | The Journal of physiology Vol. 547; no. 2; pp. 497 - 507 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
Oxford, UK
The Physiological Society
01.03.2003
Blackwell Publishing Ltd Blackwell Science Inc |
Subjects | |
Online Access | Get full text |
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Summary: | Tottering , a mouse model for absence epilepsy and cerebellar ataxia, carries a mutation in the gene encoding class A (P/Q-type) Ca 2+ channels, the dominant exocytotic Ca 2+ channel at most synapses in the mammalian central nervous system. Comparing tottering to wild-type mice, we have studied glutamatergic transmission between parallel fibres and Purkinje cells in cerebellar slices.
Results from biochemical assays and electrical field recordings demonstrate that glutamate release from parallel fibre terminals
of the tottering mouse is controlled largely by class B Ca 2+ channels (N-type), in contrast to the P/Q-channels that dominate release from wild-type terminals. Since N-channels, in a
variety of assays, are more effectively inhibited by G proteins than are P/Q-channels, we tested whether synaptic transmission
between parallel fibres and Purkinje cells in tottering mice was more susceptible to inhibitory modulation by G protein-coupled receptors than in their wild-type counterparts. GABA B receptors and α 2 -adrenergic receptors (activated by bath application of transmitters) produced a three- to fivefold more potent inhibition
of transmission in tottering than in wild-type synapses. This increased modulation is likely to be important for cerebellar transmission in vivo , since heterosynaptic depression, produced by activating GABAergic interneurones, greatly prolonged GABA B receptor-mediated presynaptic inhibition in tottering as compared to wild-type slices. We propose that this enhanced modulation shifts the balance of synaptic input to Purkinje
cells in favour of inhibition, reducing Purkinje cell output from the cerebellum, and may contribute to the aberrant motor
phenotype that is characteristic of this mutant animal. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3751 1469-7793 |
DOI: | 10.1113/jphysiol.2002.033415 |