Neurofascin and Kv7.3 are delivered to somatic and axon terminal surface membranes en route to the axon initial segment

Ion channel complexes promote action potential initiation at the mammalian axon initial segment (AIS), and modulation of AIS size by recruitment or loss of proteins can influence neuron excitability. Although endocytosis contributes to AIS turnover, how membrane proteins traffic to this proximal axonal domain is incompletely understood. Neurofascin186 (Nfasc186) has an essential role in stabilising the AIS complex to the proximal axon, and the AIS channel protein Kv7.3 regulates neuron excitability. Therefore, we have studied how these proteins reach the AIS. Vesicles transport Nfasc186 to the soma and axon terminal where they fuse with the neuronal plasma membrane. Nfasc186 is highly mobile after insertion in the axonal membrane and diffuses bidirectionally until immobilised at the AIS through its interaction with AnkyrinG. Kv7.3 is similarly recruited to the AIS. This study reveals how key proteins are delivered to the AIS and thereby how they may contribute to its functional plasticity.

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Differential Effects of Axon Initial Segment and Somatodendritic GABAA Receptors on Excitability Measures in Rat Dentate Granule Neurons

Journal of Neurophysiology ◽

10.1152/jn.00165.2010 ◽

2011 ◽

Vol 105 (1) ◽

pp. 366-379 ◽

Cited By ~ 10

Author(s):

Patricio Rojas ◽

Alejandro Akrouh ◽

Lawrence N. Eisenman ◽

Steven Mennerick

Keyword(s):

Action Potential ◽

Initial Segment ◽

Input Resistance ◽

Receptor Activation ◽

Axon Initial Segment ◽

Granule Neurons ◽

Voltage Threshold ◽

Granule Neuron ◽

Action Potential Initiation ◽

Potential Initiation

GABAA receptors are found on the somatodendritic compartment and on the axon initial segment of many principal neurons. The function of axonal receptors remains obscure, although it is widely assumed that axonal receptors must have a strong effect on excitability. We found that activation of GABAA receptors on the dentate granule neuron axon initial segment altered excitability by depolarizing the voltage threshold for action potential initiation under conditions that minimally affected overall cell input resistance. In contrast, activation of somatic GABAA receptors strongly depressed the input resistance of granule neurons without affecting the voltage threshold of action potential initiation. Although these effects were observed over a range of intracellular chloride concentrations, average voltage threshold was unaffected when ECl rendered GABAA axon initial segment responses explicitly excitatory. A compartment model of a granule neuron confirmed these experimental observations. Low ambient agonist concentrations designed to activate granule neuron tonic currents did not stimulate axonal receptors sufficiently to raise voltage threshold. Using excitatory postsynaptic current (EPSC)-like depolarizations, we show physiological consequences of axonal versus somatic GABAA receptor activation. With axonal inhibition, individual excitatory postsynaptic potentials (EPSPs) largely retained their amplitude and time course, but EPSPs that were suprathreshold under basal conditions failed to reach threshold with GABAA activation. By contrast, somatic inhibition depressed individual EPSPs because of strong shunting. Our results suggest that axonal GABAA receptors have a privileged effect on voltage threshold and that two major measures of neuronal excitability, voltage threshold and rheobase, are differentially affected by axonal and somatic GABAA receptor activation.

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Serotonin spillover onto the axon initial segment of motoneurons induces central fatigue by inhibiting action potential initiation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1216150110 ◽

2013 ◽

Vol 110 (12) ◽

pp. 4774-4779 ◽

Cited By ~ 74

Author(s):

F. Cotel ◽

R. Exley ◽

S. J. Cragg ◽

J.-F. Perrier

Keyword(s):

Action Potential ◽

Initial Segment ◽

Central Fatigue ◽

Axon Initial Segment ◽

Inhibiting Action ◽

Action Potential Initiation ◽

Potential Initiation

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Plasticity of the Axon Initial Segment: Fast and Slow Processes with Multiple Functional Roles

The Neuroscientist ◽

10.1177/1073858416648311 ◽

2016 ◽

Vol 23 (4) ◽

pp. 364-373 ◽

Cited By ~ 15

Author(s):

Anders Victor Petersen ◽

Florence Cotel ◽

Jean-François Perrier

Keyword(s):

Initial Segment ◽

Structural Changes ◽

Neuronal Excitability ◽

Local Density ◽

Axon Initial Segment ◽

Metabotropic Receptors ◽

Physiological Functions ◽

Functional Roles ◽

Action Potential Initiation ◽

Potential Initiation

The axon initial segment (AIS) is a key neuronal compartment because it is responsible for action potential initiation. The local density of Na+ channels, the biophysical properties of K+ channels, as well as the length and diameter of the AIS determine the spiking of neurons. These parameters undergo important modifications during development. The development of the AIS is governed by intrinsic mechanisms. In addition, surrounding neuronal networks modify its maturation. As a result, neurons get tuned to particular physiological functions. Neuronal activity also influences the morphology of the mature AIS. When excitatory neurons are hyperactive, their AIS undergo structural changes that decrease their excitability and thereby maintain the activity within a given range. These slow homeostatic regulatory mechanisms occur on a time scale of hours or days. In contrast, the activation of metabotropic receptors modulates the properties of ion channels expressed at the AIS within seconds and consequently produces fast adjustments of neuronal excitability. Recent results suggest that this plasticity plays important roles in physiological functions as diverse as memory formation, hearing, and motor control.

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