RAPID COMMUNICATION Periodicity of Thalamic Spindle Waves Is Abolished by ZD7288, a Blocker of Ih

Lüthi, Anita, Thierry Bal, and David A. McCormick. Periodicanisms underlying the slow (0.05–0.2 Hz) recurrence of ity of thalamic spindle waves is abolished by ZD7288, a blocker spindle waves (Bal and McCormick 1996). Spindle waves of Ih . J. Neurophysiol. 79: 3284–3289, 1998. The actions of the are generated as a circuitous interaction between thalamocornovel bradycardiac agent ZD7288 [4-(N-ethyl-N-phenylamino)tical neurons and the inhibitory GABAergic cells of the peri1,2-dimethyl-6-(methylamino)pyrimidinium chloride] were ingeniculate/ thalamic reticular nuclei (Bal et al. 1995a,b; Stervestigated on the hyperpolarization-activated cation current Ih and iade et al. 1993a). The arrival of repetitive inhibitory poston network activity in spontaneously spindling ferret lateral genicusynaptic potentials (IPSPs) concomitantly with increases in late (LGNd) slices in vitro using intracellular recording techniques. intracellular Ca due to rebound Ca spikes during spindle In voltage-clamp recordings, local application of ZD7288 (1 mM waves leads to activation and upregulation of the hyperpolarin micropipette) resulted in a complete block of Ih , whereas in current-clamp recordings, application of this agent resulted in an ization-activated mixed cationic current known as Ih (Bal abolition of the depolarizing sag activated by hyperpolarization and McCormick 1996; Lüthi and McCormick 1998; McCorand decreased the frequency of intrinsic d-oscillations for which mick and Pape 1990; Pape 1996). Persistent activation of Ih acts as a pacemaker current. In addition, block of Ih with ZD7288 Ih depolarizes thalamocortical neurons to such an extent that resulted in an abolition of the afterdepolarization (ADP) that folthey no longer respond to these IPSPs with the generation lows repetitive hyperpolarization and rebound burst firing as well of rebound Ca spikes, thus resulting in the decrement or as that occurring in between spindle waves. The block of the ADP ‘‘waning’’ of spindle waves (Bal and McCormick 1996; was associated with a block of the spindle wave refractory period Lüthi and McCormick 1998). Thus the rhythmicity of spinsuch that continuous 6to 10-Hz oscillations were generated dle waves and the refractory period may be generated in throughout the network. These findings give further support to the large part via periodic activation of Ih . hypothesis that Ih is critically involved in the generation of slow rhythmicity in synchronized thalamic activity. Support for this hypothesis has been obtained from experiments blocking Ih with extracellular application of Cs / (Bal and McCormick 1996), as well as enhancing of Ih via serotoI N T R O D U C T I O N nin and norepinephrine (Lee and McCormick 1996). Thus the block of Ih with application of low concentrations of Cs / A prominent feature of thalamocortical networks is the results in an abolition of the slow periodicities in spindle generation of various patterns of normal and pathological wave generation such that spindle waves are generated in a synchronized network oscillations (Avoli et al. 1990; continuous manner and enhancement of Ih with serotonin McCormick and Bal 1997; Niedermeyer 1990; Steriade et or norepinephrine results in the abolition of spindle waves al. 1993a). Many of these network oscillations contain lowthrough the depolarization of thalamocortical neurons. frequency components (e.g., 0.1–1 Hz) in which synchroThe drug ZD7288 is a bradycardiac agent with a selectivnized neuronal activity is interspersed with periods of quiesity for the cardiac equivalent of Ih , the pacemaker current cence or less synchronized activity. For example, spindle I f (BoSmith et al. 1993). This drug also blocks Ih in guinea waves appear as a 1to 3-s period of 6to 14-Hz synchropig substantia nigra neurons, rat hippocampal CA1 cells, and nized oscillatory activity that recurs approximately once evcat ventrobasal thalamocortical neurons with minor effects ery 5–20 s (Contreras et al. 1997; Steriade and Deschênes on other membrane properties (Gasparini and di Francesco 1984; Steriade et al. 1993a). In between spindle waves, 1997; Harris and Constanti 1995; Williams et al. 1997). thalamocortical networks exhibit a relative refractory period, Here we reinvestigated the functional properties of Ih in the strength of which depends on the period of time that has thalamocortical neurons and its role in spindle wave generapassed since the last generation of a spindle wave (Contreras tion by blocking this current with ZD7288. et al. 1997; Kim et al. 1995). Additional examples of period-