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Received April 3, 2006
Revised April 21, 2006
Accepted after revision May 5, 2006
1 University of Pavia
2 Universita di Pavia
* To whom correspondence should be addressed. E-mail: lforti{at}unipv.it.
Although Golgi cells (GoCs), the main type of inhibitory interneuron in the cerebellar granular layer (GL), are thought to play a central role for cerebellar network function, their excitable properties remained unexplored. GoCs fire rhythmically in vivo and in slices, but it was unclear whether this activity originated from pacemaker ionic mechanisms. We explored this issue in acute cerebellar slices from three week old rats by combining loose cell-attached (LCA) and whole-cell (WC) recordings. GoCs displayed spontaneous firing at 1-10 Hz (room temeperature) and 2-20 Hz (35-37°C), which persisted in the presence of blockers of fast synaptic receptors and mGluR and GABAB receptors, thus behaving, in our conditions, as pacemaker neurons. ZD 7288 (20 µM), a potent Ih blocker, slowed-down pacemaker frequency. The role of subthreshold Na+ currents (INa,sub) could not be tested directly, but we observed a robust TTx-sensitive, non-inactivating Na+ current in the subthreshold voltage range. When studying repolarising currents, we found that retigabine (5 µM), an activator of KCNQ K+ channels generating neuronal IM currents, reduced GoC excitability in the threshold region. The KCNQ channel antagonist XE991 (5 µM) did not modify firing, suggesting that GoC IM has low XE991 sensitivity. Spike repolarisation was followed by an after-hyperpolarisation (AHP) supported by apamin-sensitive Ca2+-dependent K+ currents (Iapa). Block of Iapa decreased pacemaker precision without altering average frequency. We propose that feed-forward depolarisation is sustained by Ih and INa,sub and that delayed repolarising feed-back involves an IM-like current whose properties remain to be characterised. The multiple ionic mechanisms shown here to contribute to GoC pacemaking should provide the substrate for fine regulation of firing frequency and precision, thus influencing the cyclic inhibition exerted by GoCs onto the cerebellar GL.
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