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This Article Full Text Full Text (PDF) All Versions of this Article: 99/5/2203    most recent 01065.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Shin, D. S. Articles by Carlen, P. L. PubMed PubMed Citation Articles by Shin, D. S. Articles by Carlen, P. L.

Enhanced I_h Depresses Rat Entopeduncular Nucleus Neuronal Activity From High-Frequency Stimulation or Raised K_e⁺

¹Division of Fundamental Neurobiology, Toronto Western Research Institute, Toronto Western Hospital, University Health Network; and ²Department of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Ontario, Canada

Submitted 25 September 2007; accepted in final form 25 February 2008

High-frequency stimulation (HFS) is used to treat a variety of neurological diseases, yet its underlying therapeutic action is not fully elucidated. Previously, we reported that HFS-induced elevation in [K⁺]_e or bath perfusion of raised K_e⁺ depressed rat entopeduncular nucleus (EP) neuronal activity via an enhancement of an ionic conductance leading to marked depolarization. Herein, we show that the hyperpolarization-activated (I_h) channel mediates the HFS- or K⁺-induced depression of EP neuronal activity. The perfusion of an I_h channel inhibitor, 50 µM ZD7288 or 2 mM CsCl, increased input resistance by 23.5 ± 7% (ZD7288) or 35 ± 10% (CsCl), hyperpolarized cells by 3.4 ± 1.7 mV (ZD7288) or 2.3 ± 0.9 mV (CsCl), and decreased spontaneous action potential (AP) frequency by 51.5 ± 12.5% (ZD7288) or 80 ± 13.5% (CsCl). The I_h sag was absent with either treatment, suggesting a block of I_h channel activity. Inhibition of the I_h channel prior to HFS or 6 mM K⁺ perfusion not only prevented the previously observed decrease in AP frequency, but increased neuronal activity. Under voltage-clamp conditions, I_h currents were enhanced in the presence of 6 mM K⁺. Calcium is also involved in the depression of EP neuronal activity, since its removal during raised K_e⁺ application prevented this attenuation and blocked the I_h sag. We conclude that the enhancement of I_h channel activity initiates the HFS- and K⁺-induced depression of EP neuronal activity. This mechanism could underlie the inhibitory effects of HFS used in deep brain stimulation in output basal ganglia nuclei.