The mammalian cortex is densely populated by extensively branching, thin, unmyelinated axons that form en passant synapses. Some thin axons in the peripheral nervous system hyperpolarize if action potential frequency exceeds 1-5 Hz. To test the hypothesis that cortical axons also show activity-induced hyperpolarization, we recorded extracellularly from individual CA3 pyramidal neurons while activating their axon with trains consisting of 30 electrical stimuli. Synaptic excitation was blocked by kynurenic acid. We observed a positive correlation between stimulation strength and the number of consecutive axonal stimuli that resulted in soma spikes, suggesting that the threshold increased as a function of the number of spikes. During trains without response failures there was always a cumulative increase in the soma response latency. Intermittent failures, however, decreased the latency of the subsequent response. At frequencies of > 1 Hz, the threshold and latency increases were enhanced by blocking the hyperpolarization-activated H current (Ih)by applying the specific Ih blocker ZD7288 (25 microM) or 2 mM Cs+. Under these conditions, response failures occurred after 15-25 stimuli, independent of the stimulation strength. Adding GABA receptor blockers (saclofen and bicuculline) and a blocker of metabotropic glutamate receptors did not change the activity-induced latency increase in recordings of the compound action potential. We interpret these results as an activity-induced hyperpolarization that is partly counteracted by Ih. Such a hyperpolarization may influence transmitter release and the conduction reliability of these axons.

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Most axons in the mammalian brain are unmyelinated and thin with pre-synaptic specializations (boutons) along their entire paths. The parallel fibers in the cerebellum are examples of such axons. Unlike most thin axons they have only one branch point. The granule cell soma, where they originate, can fire bursts of action potentials with spike intervals of about 2 ms. An important question is whether the axons are able to propagate spikes with similarly short intervals. By using extracellular single-unit and population-recording methods we showed that parallel fibers faithfully conduct spikes at high frequencies over long distances. However, when adding 20 microm ZD7288 or 1 mm Cs(+), or reducing the temperature from 35 to 24 degrees C, the action potentials often failed even when successfully initiated. Ba(2+)(1 mm), which blocks Kir channels, did not reproduce these effects. The conduction velocity was reduced by ZD7288 but not by Ba(2+). This suggests that the parallel fibers have an H-current that is active at rest and that is important for their frequency-following properties. Interestingly, failures occurred only when the action potential had to traverse the axonal branch point, suggesting that the branch point is the weakest point in these axons.

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