Submitted on September 25, 2007
Accepted on February 25, 2008
Enhanced Ih depresses rat entopeduncular nucleus neuronal activity from high frequency stimulation or raised K+e
Damian Seung-Ho Shin1* and Peter L Carlen1
1 Division of Fundamental Neurobiology, Toronto Western Research Institute, Toronto Western Hospital, Toronto, Canada
* To whom correspondence should be addressed. E-mail: damian.shin{at}uhnresearch.ca.
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 (Ih) channel mediates the HFS or K+-induced depression of EP neuronal activity. The perfusion of an Ih 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 Ih sag was absent with either treatment suggesting a block of Ih channel activity. Inhibition of the Ih 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, Ih 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 Ih sag. We conclude that enhancement of Ih 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.
