Ionic mechanisms of autorhythmic firing in cerebellar Golgi cells

Although Golgi cells (GoCs), the main type of inhibitory interneuron in the cerebellar granularlayer (GL), are thought to play a central role in cerebellar network function, their excitableproperties have remained unexplored. GoCs fire rhythmicallyin vivoand in slices, but it wasunclear whether this activity originated from pacemaker ionic mechanisms. We explored thisissue in acute cerebellar slices from 3-week-oldrats by combining loose cell-attached (LCA) andwhole-cell (WC) recordings. GoCs displayed spontaneous firing at 1–10 Hz (room temperature)and 2–20 Hz (35–37◦C), which persisted in the presence of blockers of fast synaptic receptors andmGluR and GABABreceptors, thus behaving, in our conditions, as pacemaker neurons. ZD 7288(20μM), a potent hyperpolarization-activated current (Ih) blocker, slowed down pacemakerfrequency. The role of subthreshold Na+currents (INa,sub) could not be tested directly, butwe observed a robust TTX-sensitive, non-inactivating Na+current in the subthreshold voltagerange. When studying repolarizing currents, we found that retigabine (5μM), an activator ofKCNQ K+channels generating neuronal M-type K+(IM) currents, reduced GoC excitabilityin the threshold region. The KCNQ channel antagonist XE991 (5μM) did not modify firing,suggesting that GoCIMhas low XE991 sensitivity. Spike repolarization was followed by anafter-hyperpolarization (AHP) supported by apamin-sensitive Ca2+-dependent K+currents(Iapa). Block ofIapadecreased pacemaker precision without altering average frequency. Wepropose that feed-forward depolarization is sustained byIhandINa,sub, and that delayedrepolarizing feedback involves anIM-like current whose properties remain to be characterized.The multiple ionic mechanisms shown here to contribute to GoC pacemaking should providethe substrate for fine regulation of firing frequency and precision, thus influencing the cyclicinhibition exerted by GoCs onto the cerebellar GL.