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  • Title: Enhanced Ih depresses rat entopeduncular nucleus neuronal activity from high-frequency stimulation or raised Ke+.
    Author: Shin DS, Carlen PL.
    Journal: J Neurophysiol; 2008 May; 99(5):2203-19. PubMed ID: 18305090.
    Abstract:
    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 microM 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.
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