Synaptic Integration in Cerebellar Nucleus Neurons and its Modulation by 5-HT.
Hertie-Institute for Clinical Brain Research, Dept. Cognitive Neurology, Tuebingen , Germany
Neurons of the cerebellar nuclei (CN) integrate excitatory input from mossy and climbing fiber collaterals and inhibitory input from Purkinje cells generating the final output of the cerebellum. The most prominent modulatory input that CN neurons receive originates from serotoninergic neurons of raphe nuclei. Its functional role is basically unknown but an elevated cerebellar serotonin (5-HT) level during motor activity illustrates its functional relevance. Using dynamic clamp in vitro we investigated the processing of synaptic input in CN neurons and its modulation by 5-HT.
The relative contribution of inhibitory and excitatory inputs to the control of CN activity is still an open question. The convergence of Purkinje cells and their ongoing activity in vivo suggest a substantial baseline of inhibitory input to CN neurons. Stimulating CN neurons with such an inhibitory baseline in dynamic clamp experiments resulted in a complete cessation of CN spiking. CN neurons posses intrinsic properties that allow them to generate ongoing spiking activity in the absence of any input but synaptic excitation was required in addition to intrinsic excitation to overcome the barrage of synaptic inhibition to produce an ongoing baseline activity of CN neurons.
The synaptic input to CN neurons is characterized by a specific set of properties. Inhibitory input from Purkinje cells is mediated exclusively by fast GABA A-type synapses and excitatory input from mossy and/or climbing fibers has a strong NMDA component with low voltage dependence. We investigated the relevance of these properties for the signal transduction performed by CN neurons and found that it facilitated the access of dis-inhibition to the control of CN activity. The most important factor for an increased impact of dis-inhibition versus excitation was the slow NMDA time course. The function of the NMDA voltage dependence was twofold. Its comparatively weak inactivation provided a baseline of synaptic excitation even at hyperpolarized potentials. This baseline prevented most likely a membrane bi-stability that could result in principle from a large NMDA component. At the same time however, the NMDA voltage dependence was strong enough to amplify depolarizing input regardless of its origin, i.e. excitation and/or dis-inhibition.
Serotonin represents the most salient input to the CN besides mossy/climbing fiber and purkinje cell input. The signal processing properties outlined in the former paragraph were confirmed under the influence of 5-HT. Current clamp and voltage clamp experiments revealed multiple effects of 5-HT on the intrinsic excitability of CN neurons. Their combined action resulted in an activity dependent modulation of CN signal processing. The effect of 5-HT depended on the balance between excitation and inhibition and on the absolute synaptic strength for a given balance, corresponding to the strength of shunting. Overall, 5-HT shifted the operation range of CN neurons towards input regimes with higher inhibitory activity. Therefore, 5-HT might adjust the excitability of CN neurons to an elevated level of inhibition during periods of raised motor activity. Furthermore, the multiple effects of 5-HT on CN excitability might provide these neurons with a mechanism of homeostatic plasticity to adjust their excitability to a given level of excitatory versus inhibitory input activity.