Disruption of the olivo-cerebellar circuit by Purkinje neuron-specific ablation of BK channels
| Autor: | Arthur Konnerth, Horst A. Henning, Yosef Yarom, Helmuth Adelsberger, Peter Ruth, Matthias Sausbier, Georg Wietzorrek, Xiaowei Chen, Yury Kovalchuk |
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| Rok vydání: | 2010 |
| Předmět: |
BK channel
Cerebellum Patch-Clamp Techniques Ataxia Action Potentials Motor Activity Inhibitory postsynaptic potential Deep cerebellar nuclei Mice Purkinje Cells medicine Animals Large-Conductance Calcium-Activated Potassium Channels Patch clamp Organic Chemicals Mice Knockout Multidisciplinary biology Muscimol Chemistry Brain Climbing fiber Anatomy Biological Sciences Immunohistochemistry Motor coordination Pyridazines medicine.anatomical_structure Cerebellar Nuclei nervous system biology.protein medicine.symptom Neuroscience |
| Zdroj: | Proceedings of the National Academy of Sciences. 107:12323-12328 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1001745107 |
| Popis: | The large-conductance voltage- and calcium-activated potassium (BK) channels are ubiquitously expressed in the brain and play an important role in the regulation of neuronal excitation. Previous work has shown that the total deletion of these channels causes an impaired motor behavior, consistent with a cerebellar dysfunction. Cellular analyses showed that a decrease in spike firing rate occurred in at least two types of cerebellar neurons, namely in Purkinje neurons (PNs) and in Golgi cells. To determine the relative role of PNs, we developed a cell-selective mouse mutant, which lacked functional BK channels exclusively in PNs. The behavioral analysis of these mice revealed clear symptoms of ataxia, indicating that the BK channels of PNs are of major importance for normal motor coordination. By using combined two-photon imaging and patch-clamp recordings in these mutant mice, we observed a unique type of synaptic dysfunction in vivo, namely a severe silencing of the climbing fiber–evoked complex spike activity. By performing targeted pharmacological manipulations combined with simultaneous patch-clamp recordings in PNs, we obtained direct evidence that this silencing of climbing fiber activity is due to a malfunction of the tripartite olivo-cerebellar feedback loop, consisting of the inhibitory synaptic connection of PNs to the deep cerebellar nuclei (DCN), followed by a projection of inhibitory DCN afferents to the inferior olive, the origin of climbing fibers. Taken together, our results establish an essential role of BK channels of PNs for both cerebellar motor coordination and feedback regulation in the olivo-cerebellar loop. |
| Databáze: | OpenAIRE |
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