Fast Delayed Rectifier Potassium Current: Critical for Input and Output of the Circadian System

Abstract

The ability to generate intrinsic circadian rhythms in electrical activity appears to be a key property of central pacemaker neurons and one essential to the function of the circadian timing system. Previous work has demonstrated that suprachiasmatic nucleus (SCN) neurons express the fast delayed rectifier (FDR) potassium current and raise questions about the function of this current. Here, we report that mice lacking both Kcnc1 and Kcnc2 genes (double knockout, dKO) fail to express the Kv3.1 and 3.2 channels in the SCN as well as exhibit a greatly reduced FDR current. SCN neurons from these dKO mice exhibit reduced spontaneous activity during the day as well as reduced NMDA-evoked excitatory responses during the night. Interestingly, the daily rhythm in PER2 expression in the SCN was not altered in the dKO mice though the photic induction of c-FOS was attenuated. Behaviorally, the dKO mice exhibited extremely disrupted daily rhythms in wheel running behavior. In a light/dark cycle, some of the dKO mice were arrhythmic while others expressed a diurnal rhythm with low amplitude and significant activity during the day. When placed in constant darkness, the dKO mice exhibited low amplitude, fragmented rhythms and attenuated light-responses. Together, this data is consistent with the hypothesis that the FDR current is critical for the generation of robust circadian rhythms in behavior as well as the synchronization of the circadian system to the photic environment.

IA Channels Encoded by Kv1.4 and Kv4.2 Regulate Neuronal Firing in the Suprachiasmatic Nucleus and Circadian Rhythms in Locomotor Activity

“…In addition, the 0.5 h shortening of the period of circadian rhythms in locomotor activity of mice lacking either Kv1.4 or Kv4.2 contrasts with the recently reported 0.5 h lengthening of the period of circadian behavior in mice lacking one copy of Scn1a, which encodes the voltage-gated sodium channel ␣ subunit, Nav1.1 (Han et al, 2012). The results here also contrast markedly with the results of several previous studies conducted on mice with other channel deficiencies, including mice lacking the large conductance, Ca 2ϩ and voltage-dependent, BK (Kcnma1); K ϩ channel subunit (Meredith et al, 2006); the voltage-gated Ca 2ϩ channel subunit, Cav2.2 (Cacna1b) (Beuckmann et al, 2003); or the Kv channel subunits, Kv3.1 and Kv3.2 (Kcnc1 and Kcnc2) (Kudo et al, 2011). In contrast with the findings here for Kv1.4…”

Na V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

“…This interpretation is consistent with the finding that TTX applied to hypothalamic slices blocks SCN action potentials but does not affect the circadian oscillation of clock genes (44), although longer-term TTX blockade may interfere with clock gene expression (7). Similarly, circadian clock gene expression does not seem to be impaired in animals with reduced delayed rectifier potassium currents (45) or aged animals (46), both of which show low-amplitude circadian rhythms. Finally, decreased amplitude of circadian locomotor activity could also result from the reduced Na V 1.1 channel activity in brain regions outside of the SCN.…”

Mis-expression of the BK K+ channel disrupts suprachiasmatic nucleus circuit rhythmicity and alters clock-controlled behavior

“…This phenotype is similar to mice with a deletion in Kcnc1/2, encoding the fast delayed rectifier Kv3.1/3.2 K ϩ current (28), which exhibit reduced frequency firing during the day. In flies, overexpression of the Shaw K ϩ channel also results in increased locomotor activity, presumably through suppression of neuronal excitability (21).…”

“…Since alterations of K ϩ currents have not been shown to disrupt clock gene-based time-encoding (Fig. 3E) (14,28,41), the core clock could still express rhythms via coupling to another cellular output.…”

“…However, rhythms generated from a low amplitude oscillator are unlikely to promote survival in the wild due to inappropriately bounded activity durations and increased sensitivity to environmental perturbation. Diurnal variation in the membrane K ϩ current, which is conserved among flies (14,21,48), mollusk (42), and mouse (28,41), is a primary contributor to behavioral robustness. Tg-BK R207Q mice provide a novel model to explore the performance of a low amplitude circuit further, with respect to membrane and behavioral rhythmicity.…”