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Abstract

The axon initial segment (AIS) is a specialized region in neurons where action potentials are initiated. It is commonly assumed that this process requires a high density of voltage-gated sodium (Na(+)) channels. Paradoxically, the results of patch-clamp studies suggest that the Na(+) channel density at the AIS is similar to that at the soma and proximal dendrites. Here we provide data obtained by antibody staining, whole-cell voltage-clamp and Na(+) imaging, together with modeling, which indicate that the Na(+) channel density at the AIS of cortical pyramidal neurons is approximately 50 times that in the proximal dendrites. Anchoring of Na(+) channels to the cytoskeleton can explain this discrepancy, as disruption of the actin cytoskeleton increased the Na(+) current measured in patches from the AIS. Computational models required a high Na(+) channel density (approximately 2,500 pS microm(-2)) at the AIS to account for observations on action potential generation and backpropagation. In conclusion, action potential generation requires a high Na(+) channel density at the AIS, which is maintained by tight anchoring to the actin cytoskeleton.

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Active propagation of somatic action potentials into neocortical pyramidal cell dendrites.

B. Sakmann, G Stuart (1994)

The dendrites of neurons in the mammalian central nervous system have been considered as electrically passive structures which funnel synaptic potentials to the soma and axon initial segment, the site of action potential initiation. More recent studies, however, have shown that the dendrites of many neurons are not passive, but contain active conductances. The role of these dendritic voltage-activated channels in the initiation of action potentials in neurons is largely unknown. To assess this directly, patch-clamp recordings were made from the dendrites of neocortical pyramidal cells in brain slices. Voltage-activated sodium currents were observed in dendritic outside-out patches, while action potentials could be evoked by depolarizing current pulses or by synaptic stimulation during dendritic whole-cell recordings. To determine the site of initiation of these action potentials, simultaneous whole-cell recordings were made from the soma and the apical dendrite or axon of the same cell. These experiments showed that action potentials are initiated first in the axon and then actively propagate back into the dendritic tree.

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The NEURON Book

Nicholas Carnevale, Michael L. Hines (2006)

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AnkyrinG Is Required for Clustering of Voltage-gated Na Channels at Axon Initial Segments and for Normal Action Potential Firing

Daixing Zhou, Stephen Lambert, Peter L. Malen … (1998)

Voltage-gated sodium channels (NaCh) are colocalized with isoforms of the membrane-skeletal protein ankyrinG at axon initial segments, nodes of Ranvier, and postsynaptic folds of the mammalian neuromuscular junction. The role of ankyrinG in directing NaCh localization to axon initial segments was evaluated by region-specific knockout of ankyrinG in the mouse cerebellum. Mutant mice exhibited a progressive ataxia beginning around postnatal day P16 and subsequent loss of Purkinje neurons. In mutant mouse cerebella, NaCh were absent from axon initial segments of granule cell neurons, and Purkinje cells showed deficiencies in their ability to initiate action potentials and support rapid, repetitive firing. Neurofascin, a member of the L1CAM family of ankyrin-binding cell adhesion molecules, also exhibited impaired localization to initial segments of Purkinje cell neurons. These results demonstrate that ankyrinG is essential for clustering NaCh and neurofascin at axon initial segments and is required for physiological levels of sodium channel activity.