TY - JOUR T1 - Acute Knockdown of Kv4.1 Regulates Repetitive Firing Rates and Clock Gene Expression in the Suprachiasmatic Nucleus and Daily Rhythms in Locomotor Behavior JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0377-16.2017 SP - ENEURO.0377-16.2017 AU - Tracey O. Hermanstyne AU - Daniel Granados-Fuentes AU - Rebecca L. Mellor AU - Erik D. Herzog AU - Jeanne M. Nerbonne Y1 - 2017/05/12 UR - http://www.eneuro.org/content/early/2017/05/12/ENEURO.0377-16.2017.abstract N2 - Rapidly activating and inactivating A-type K+ currents (IA) encoded by Kv4.2 and Kv4.3 pore-forming (α) subunits of the Kv4 subfamily are key regulators of neuronal excitability. Previous studies have suggested a role for Kv4.1 α-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 non-targeted shRNA-expressing SCN neurons (day: 3.1 ± 0.5 Hz; night: 1.6 ± 0.3 Hz). IA 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 non-targeted 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 (2256 ± 166 MΩ), compared to non-targeted shRNA-expressing SCN neurons (1143 ± 93 MΩ). Additional experiments revealed that acute knockdown of Kv4.1 significantly (P < 0.01) shortened, by ∼0.5 hr, 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.Significance Statement Neurons in the suprachiasmatic nucleus (SCN) use a transcription-translation feedback loop to generate daily changes in input resistances and firing rates that drive rhythms in physiology and behavior, although the molecular determinants underlying the daily changes in membrane properties have not been identified. We show here that Kv4.1 contributes to the generation of IA and the regulation of the circadian period of electrical activity and clock gene expression in SCN neurons as well as locomotor behavior. These observations provide the first demonstration of a physiologic role for Kv4.1-encoded IA channels in the mammalian brain. In addition, we show that the effects of Kv4.1 knockdown on IA, input resistances and repetitive firing rates are greater at night than during the day. ER -