PRESYNAPTIC ORIGIN OF PAIRED-PULSE DEPRESSION AT CLIMBING FIBER PURKINJE-CELL SYNAPSES IN THE RAT CEREBELLUM

1. Climbing fibre-mediated excitatory postsynaptic potentials (CF-EPSP s) or currents (CF-EPSCs) were recorded from Purkinje cells in rat cer ebellar slices using the whole-cell recording technique. 2. Climbing f ibre responses displayed prominent paired-pulse depression (PPD). In t he current-clamp recording mode, PPD resulted in a decreased number of spikelets in the second complex spike of the pair, and depression of the after-depolarization and after-hyperpolarization. 3. The mechanism of PPD was examined under voltage clamp. Manipulations that reduce tr ansmitter release significantly affected PPD. These included lowering extracellular Ca2+ concentration and bath application of baclofen or a denosine. 4. Changing the number of stimulated climbing fibres, equiva lent to changing the number of release sites, had no effect on PPD. 5. Selective manipulations of postsynaptic responsiveness had no effect on PPD. These included partial blockade of CF-EPSCs by a non-NMDA rece ptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and chan ging the holding potential. 6. A rapidly dissociating AMPA receptor an tagonist, 2,3-cis-piperidine dicarboxylic acid, inhibited the second C F-EPSC of the pair proportionately more than the first, suggesting tha t presynaptic release by the second pulse is decreased. 7. PPD at inte rstimulus intervals of 50 ms or longer (up to 3000 ms) was not signifi cantly affected by manipulations that change postsynaptic glutamate re ceptor desensitization. 8. Blockade of metabotropic glutamate, GABA(B) and adenosine receptors had no effect on PPD, suggesting that presyna ptic autoreceptors do not contribute to PPD. 9. These results indicate that decreased transmitter release is a major cause of PPD at cerebel lar climbing fibre-Purkinje cell synapses.