Somatodendritic Kv7/KCNQ/M channels control interspike interval in hippocampal interneurons

The M-current (I-M), comprised of Kv7 channels, is a voltage-activated K+ conductance that plays a key role in the control of cell excitability. In hippocampal principal cells, I-M controls action potential (AP) accommodation and contributes to the medium-duration after hyperpolarization, but the role of I-M in control of interneuron excitability remains unclear. Here, we investigated I-M in hippocampal stratum oriens (SO) interneurons, both from wild-type and transgenic mice in which green fluorescent protein (GFP) was expressed in somatostatin-containing interneurons. Somatodendritic expression of Kv7.2 or Kv7.3 subunits was colocalized in a subset of GFP + SO interneurons, corresponding to oriens-lacunosum moleculare (O-LM) cells. Under voltage clamp (VC) conditions at -30 mV, the Kv7 channel antagonists linopirdine/XE-991 abolished the I-M amplitude present during relaxation from -30 to -50 mV and reduced the holding current (I-hold). In addition, 0.5 mM tetraethylammonium reduced I-M, suggesting that I-M was composed of Kv7.2-containing channels. In contrast, the Kv7 channel opener retigabine increased I-M amplitude and Ihold. When strongly depolarized in VC, the linopirdine-sensitive outward current activated rapidly and comprised up to 20% of the total current. In current-clamp recordings from GFP + SO cells, linopirdine induced depolarization and increased AP frequency, whereas retigabine induced hyperpolarization and arrested firing. In multicompartment O-LM interneuron models that incorporated I-M, somatodendritic placement of Kv7 channels best reproduced experimentally measured I-M. The models suggest that Kv3- and Kv7-mediated channels both rapidly activate during single APs; however, Kv3 channels control rapid repolarization of the AP, whereas Kv7 channels primarily control the interspike interval.