Abstract
Parkinson's disease is a common neurodegenerative disorder characterized by a profound motor disability that is traceable to the emergence of synchronous, rhythmic spiking in neurons of the external segment of the globus pallidus (GPe). The origins of this pathophysiology are poorly defined for the generation of pacemaking. After the induction of a parkinsonian state in mice, there was a progressive decline in autonomous GPe pacemaking, which normally serves to desynchronize activity. The loss was attributable to the downregulation of an ion channel that is essential in pacemaking, the hyperpolarization and cyclic nucleotide–gated (HCN) channel. Viral delivery of HCN2 subunits restored pacemaking and reduced burst spiking in GPe neurons. However, the motor disability induced by dopamine (DA) depletion was not reversed, suggesting that the loss of pacemaking was a consequence, rather than a cause, of key network pathophysiology, a conclusion that is consistent with the ability of L-type channel antagonists to attenuate silencing after DA depletion.
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Acknowledgements
We thank Y. Chen, K. Saporito and S. Ulrich for technical assistance. This work was supported by grants from the Parkinson's Disease Foundation and American Parkinson Disease Association Research to C.S.C.; a grant from the Michael J. Fox Foundation to P.O.; a grant from the Hartmann Foundation to D.J.S. and US National Institutes of Health grants NS069777 to C.S.C., MH082522 to T.S.G., NS064757 to A.S.L., NS05595 and NS059934 to D.M.C., NS042762 to H.K. and NS047085 to D.J.S.
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C.S.C. and D.J.S. conceived the study, designed the experiments and directed the project. K.E.G. and P.O. designed the viral expression strategy and generated and validated the HCN2 vectors in vitro and in vivo. C.S.C., T.S.G., J.N.G., J.N.M. and H.K. carried out the recordings. A.S.L., R.S. and D.M.C. provided HCN mutants, generated the antibodies and carried out the western blots. C.S.C., A.B.G. and K.E.G. designed the probes and carried out the qPCRs. T.T. participated in the exploratory phase of the qPCR experiments. K.E.G and S.M.F. carried out the behavioral analyses. C.S.C. and D.J.S. wrote the paper. All authors discussed the results and implications and commented on the manuscript at all stages.
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Chan, C., Glajch, K., Gertler, T. et al. HCN channelopathy in external globus pallidus neurons in models of Parkinson's disease. Nat Neurosci 14, 85–92 (2011). https://doi.org/10.1038/nn.2692
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DOI: https://doi.org/10.1038/nn.2692
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