Slow inactivation of Na+ current and slow cumulative spike adaptation in mouse and guinea‐pig neocortical neurones in slices.

1. Spike adaptation of neocortical pyramidal neurones was studied with sharp electrode recordings in slices of guinea‐pig parietal cortex and whole‐cell patch recordings of mouse somatosensory cortex. Repetitive intracellular stimulation with 1 s depolarizing pulses delivered at intervals of < 5 s caused slow, cumulative adaptation of spike firing, which was not associated with a change in resting conductance, and which persisted when Co2+ replaced Ca2+ in the bathing medium. 2. Development of slow cumulative adaptation was associated with a gradual decrease in maximal rates of rise of action potentials, a slowing in the post‐spike depolarization towards threshold, and a positive shift in the threshold voltage for the next spike in the train; maximal spike repolarization rates and after‐hyperpolarizations were unchanged. 3. The data suggested that slow adaptation reflects use‐dependent removal of Na+ channels from the available pool by an inactivation process which is much slower than fast, Hodgkin‐Huxley‐type inactivation. 4. We therefore studied the properties of Na+ channels in layer II‐III mouse neocortical cells using the cell‐attached configuration of the patch‐in‐slice technique. These had a slope conductance of 18 +/‐ 1 pS and an extrapolated reversal potential of 127 +/‐ 6 mV above resting potential (Vr) (mean +/‐ S.E.M.; n = 5). Vr was estimated at ‐72 +/‐ 3 mV (n = 8), based on the voltage dependence of the steady‐state inactivation (h infinity) curve. 5. Slow inactivation (SI) of Na+ channels had a mono‐exponential onset with tau on between 0.86 and 2.33 s (n = 3). Steady‐state SI was half‐maximal at ‐43.8 mV and had a slope of 14.4 mV (e‐fold)‐1. Recovery from a 2 s conditioning pulse was bi‐exponential and voltage dependent; the slow time constant ranged between 0.45 and 2.5 s at voltages between‐128 and ‐68 mV. 6. The experimentally determined parameters of SI were adequate to simulate slow cumulative adaptation of spike firing in a single‐compartment computer model. 7. Persistent Na+ current, which was recorded in whole‐cell configuration during slow voltage ramps (35 mV s‐1), also underwent pronounced SI, which was apparent when the ramp was preceded by a prolonged depolarizing pulse.