Functional role of the fast transient outward K⁺ current I _A in pyramidal neurons in (rat) primary visual cortex

A molecular genetic approach was exploited to directly test the hypothesis that voltage-gated K⁺(Kv) channel pore-forming (a) subunits of the Kv4 subfamily encode the fast transient outward K⁺ current (I _A ) in cortical pyramidal neurons and to explore the functional role of I_A in shaping action potential waveforms and in controlling repetitive firing in these cells. Using the biolistic gene gun, cDNAs encoding a mutant Kv4.2 α subunit (Kv4.2W362F), which functions as a dominant negative (Kv4.2DN), and enhanced green fluorescent protein (EGFP) were introduced in vitro into neurons isolated from postnatal rat primary visual cortex. Whole-cell voltage-clamp recordings obtained from EGFP-positive pyramidal neurons revealed that I_A is selectively eliminated in cells expressing Kv4.2DN. The densities and properties of the other Kv currents are unaffected. In neurons expressing Kv4.2DN, input resistances are increased and the (current) thresholds for action potential generation are decreased. In addition, action potential durations are prolonged, the amplitudes of after-hyperpolarizations are reduced, and the responses to prolonged depolarizing inputs are altered markedly in cells expressing Kv 4.2DN. At low stimulus intensities, firing rates are increased in Kv4.2DN-expressing cells, whereas at high stimulus intensities, Kv4.2DN-expressing cells adapt strongly. Together, these results demonstrate that Kv4 α subunits encode I _A channels and that I_A plays a pivotal role in shaping the waveforms of individual action potentials and in controlling repetitive firing in visual cortical pyramidal neurons.