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Resistance to action potential depression of a rat axon terminal in vivo

Significance During high-frequency firing, the shape of a presynaptic action potential (AP) can alter, thereby changing neurotransmitter release. In this paper, we describe how a giant terminal in the brainstem of newborn rats called the calyx of Held can fire in vivo at high frequencies without substantial AP depression. The underlying mechanism was found to be the presence of sodium channels that can recover rapidly from depression in combination with a close match between the potential that is attained following an AP with the potential that maximizes AP stability. Surprisingly, this match was already there shortly after formation of the calyx of Held. We speculate that these mechanisms help synapses to maximize timing precision during high-frequency firing. The shape of the presynaptic action potential (AP) has a strong impact on neurotransmitter release. Because of the small size of most terminals in the central nervous system, little is known about the regulation of their AP shape during natural firing patterns in vivo. The calyx of Held is a giant axosomatic terminal in the auditory brainstem, whose biophysical properties have been well studied in slices. Here, we made whole-cell recordings from calyceal terminals in newborn rat pups. The calyx showed a characteristic burst firing pattern, which has previously been shown to originate from the cochlea. Surprisingly, even for frequencies over 200 Hz, the AP showed little or no depression. Current injections showed that the rate of rise of the AP depended strongly on its onset potential, and that the membrane potential after the AP (Vafter) was close to the value at which no depression would occur during high-frequency activity. Immunolabeling revealed that Nav1.6 is already present at the calyx shortly after its formation, which was in line with the fast recovery from AP depression that we observed in slice recordings. Our findings thus indicate that fast recovery from depression and an inter-AP membrane potential that minimizes changes on the next AP in vivo, together enable high timing precision of the calyx of Held already shortly after its formation.