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Received September 27, 2002
Accepted after revision December 10, 2002
1 Department of Neuroscience, Tufts University School of Medicine and Molecular Cardiology Research Institute, New England Medical Centre, Boston, MA 02111, USA
2 Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA
* To whom correspondence should be addressed. E-mail: kathleen.dunlap{at}tufts.edu.
Tottering, a mouse model for absence epilepsy and cerebellar ataxia, carries a mutation in the gene encoding class A (P/Q-type) Ca2+ channels, the dominant exocytotic Ca2+ 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 Ca2+ 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 than its wild-type counterpart to inhibitory modulation by G protein-coupled receptors. GABAB receptors and 
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 GABAB 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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