PERIODICITY OF THALAMIC SPINDLE WAVES IS ABOLISHED BY ZD7288, A BLOCKER OF I-H

The actions of the novel bradycardiac agent ZD7288 [4-(N-ethyl-N-pheny lamino)-1,2-dimethyl-6-( methylamino) pyrimidinium chloride] were inve stigated on the hyperpolarization-activated cation current I-h and on network activity in spontaneously spindling ferret lateral geniculate (LGNd) slices in vitro using intracellular recording techniques. In vo ltage-clamp recordings, local application of ZD7288 (1 mM in micropipe tte) resulted in a complete block of I-h, whereas in current-clamp rec ordings, application of this agent resulted in an abolition of the dep olarizing sag activated by hyperpolarization and decreased the frequen cy of intrinsic delta-oscillations for which I-h acts as a pacemaker c urrent. In addition, block of I-h With ZD7288 resulted in an abolition of the afterdepolarization (ADP) that follows repetitive hyperpolariz ation and rebound burst firing as well as that occurring in between sp indle waves. The block of the ADP was associated with a block of the s pindle wave refractory period such that continuous 6- to 10-Hz oscilla tions were generated throughout the network. These findings give furth er support to the hypothesis that I-h is critically involved in the ge neration of slow rhythmicity in synchronized thalamic activity.