Acute Knockdown of Kv4.1 Regulates Repetitive Firing Rates and Clock Gene Expression in the Suprachiasmatic Nucleus and Daily Rhythms in Locomotor Behavior

Rapidly activating and inactivating A-type K +/- currents (IA) encoded by Kv4.2 and Kv4.3 pore-forming (+/-) subunits of the Kv4 subfamily are key regulators of neuronal excitability. Previous studies have suggested a role for Kv4.1 +/- -subunits in regulating the firing properties of mouse suprachiasmatic nucleus (SCN) neurons. To test this, we utilized an RNA-interference strategy to knockdown Kv4.1, acutely and selectively, in the SCN. Current-clamp recordings revealed that the in vivo knockdown of Kv4.1 significantly (p +/- 0.0001) increased mean +/- SEM repetitive firing rates in SCN neurons during the day (6.4 +/- 0.5 Hz) and at night (4.3 +/- 0.6 Hz), compared with nontargeted shRNAexpressing SCN neurons (day: 3.1 +/- 0.5 Hz; night: 1.6 +/- 0.3 Hz). I-A was also significantly (p +/- 0.05) reduced in Kv4.1-targeted shRNA-expressing SCN neurons (day: 80.3 +/- 11.8 pA/pF; night: 55.3 +/- 7.7 pA/pF), compared with nontargeted shRNA-expressing (day: 121.7 +/- 10.2 pA/pF; night: 120.6 +/- 16.5 pA/pF) SCN neurons. The magnitude of the effect of Kv4.1-targeted shRNA expression on firing rates and IA was larger at night. In addition, Kv4.1-targeted shRNA expression significantly (p < 0.001) increased mean +/- SEM nighttime input resistance (R-in; 2256 +/- 166 M +/-), compared to nontargeted shRNA-expressing SCN neurons (1143 +/- 93 M +/-). Additional experiments revealed that acute knockdown of Kv4.1 significantly (p < 0.01) shortened, by similar to 0.5 h, the circadian period of spontaneous electrical activity, clock gene expression and locomotor activity demonstrating a physiological role for Kv4.1-encoded IA channels in regulating circadian rhythms in neuronal excitability and behavior.