HCN channelopathy in external globus pallidus neurons in models of Parkinson's disease

• Published in: Nature neuroscience Vol. 14; no. 1; pp. 85 - 92
• Main Authors: Surmeier, D James, Chan, C Savio, Glajch, Kelly E, Gertler, Tracy S, Guzman, Jaime N, Mercer, Jeff N, Lewis, Alan S, Goldberg, Alan B, Tkatch, Tatiana, Shigemoto, Ryuichi, Fleming, Sheila M, Chetkovich, Dane M, Osten, Pavel, Kita, Hitoshi
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2011; Nature Publishing Group
• Subjects: 631/378/1697; 631/378/2591; 631/378/2632; 692/699/375; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Calcium - metabolism; Cellular proteins; Channelopathies - physiopathology; Dependovirus - genetics; Disease Models, Animal; Dopamine - metabolism; Down-Regulation; Genetic Vectors - administration & dosage; Globus pallidus; Globus Pallidus - physiopathology; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Hypotheses; Ion channels; Ion Channels - genetics; Ion Channels - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microinjections; Neurobiology; Neurons - metabolism; Neurons - physiology; Neurosciences; Oxidopamine; Parkinson Disease - physiopathology; Parkinson's disease; Pathophysiology; Physiological aspects; Potassium Channels; Substantia Nigra - metabolism; United States; California; Chicago Illinois; United States > US; Illinois
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.2692

Using a rat model of PD, the authors find a progressive decline in autonomous globus pallidus pacemaking. This loss was reversed by viral expression of the HCN channel. However, the motor disability induced by DA depletion was not reversed, suggesting that the loss of pacemaking was a consequence, not a cause, of key network pathophysiology. 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.