Does Axon Initial Segment Plasticity Regulate Neuron Excitability?
Material below summarizes the article Neuron Morphology Influences Axon Initial Segment Plasticity, published on January 18, 2016, in eNeuro, and authored by Allan T. Gulledge and Jaime J. Bravo.
Most studies of plasticity in the nervous system focus on mechanisms regulating the synaptic connectivity between neurons. Yet plasticity in neuron function extends well beyond the synapse to include any structural or functional change that alters the way neurons transduce synaptic input into action potential output, a process known as synaptic integration.
In vertebrate neurons, the final stage of synaptic integration, the generation of action potentials, occurs in the axon initial segment (AIS). The AIS is a specialized region of the proximal axon that is enriched with the voltage-gated sodium channels (VGSCs) responsible for action potential initiation and propagation.
Because of its central role in generating action potentials, plasticity of AIS structure (“AIS plasticity”), including changes in the length or location of the AIS, is postulated to regulate the sensitivity — that is, “excitability” — of neurons to synaptic input.
While the impact of AIS structure on neuron excitability is not well understood, it is generally assumed that longer initial segments, containing more VGSCs, will enhance neuron excitability, while translocation of the AIS away from the somatodendritic source of synaptic input will reduce excitability.
However, the AIS does not exist in isolation, and somata and dendrites generate capacitive and conductive loads that influence neuron excitability by absorbing electrical currents flowing through VGSCs in the AIS.
To explore how neuron morphology influences action potential initiation in the AIS, and to better predict the functional impact of plastic changes in AIS structure, we quantified neuron excitability — that is, the minimal current stimulus necessary to initiate action potential generation — in computational models of simplified and morphologically realistic (reconstructed) neurons paired with a range of AIS architectures.
Contrary to expectations, we found that the impact of changes in AIS length or location on neuron excitability is dependent on neuron morphology. Small neurons are most excitable when the AIS is relatively short and/or located close to the soma. On the other hand, large neurons are most excitable when the AIS is longer or moved farther away from the source of synaptic input. Therefore, the impact of plastic changes in AIS structure — shortening or translocating the AIS — on neuron excitability is dictated by overall neuron size and shape.
What underlies the impact of neuron morphology on AIS performance?
Action potential initiation in the AIS starts with passive spread of excitatory synaptic signals arriving from the soma, and ends with rapid recruitment of VGSCs in the AIS. Synaptic signals become modestly reduced in amplitude as they transfer from the soma to the AIS, which will favor action potential generation when the AIS is located close to the soma.
While this “voltage attenuation” of synaptic signals in the axon is independent of neuron shape or size, the expansive somatodendritic surface areas of larger neurons generate capacitive and conductance loads that absorb electrical currents produced by VGSCs in the AIS, thereby reducing their effectiveness in generating action potentials. Moving VGSCs away from the soma by lengthening or translocating the AIS to more distal axonal locations reduces the electrical impact of somatodendritic surface areas to enhance neuron excitability.
Thus, the most excitable AIS structure is one that balances voltage attenuation of synaptic signals in the axon with distance-dependent electrical isolation from somatodendritic conductance loads. In small neurons, having tiny surface areas, shorter and more proximal initial segments reduce the impact of voltage attenuation of synaptic signals. In larger neurons, excitability is promoted by longer and/or more distal initial segments that electrically isolate VGSCs from the soma and dendrites.
Is AIS plasticity effective in regulating neuron excitability?
Overall, we find that changes in AIS location have only modest impact on neuron excitability, with translocations of up to 15 µm generating only small (less than five percent) changes in the minimal stimulus necessary to drive action potential generation. Changes in AIS length are somewhat more effective, with 50 percent increases or decreases in AIS length producing up to a 20 percent change in minimal stimulus threshold.
Overall, our results demonstrate that the impact of AIS plasticity on neuron excitability depends critically on neuron morphology, and that changes in AIS length, with corresponding changes in the total number of VGSCs, will be more effective than AIS translocations in regulating neuron excitability.
Neuron Morphology Influences Axon Initial Segment Plasticity. Allan T. Gulledge, Jaime J. Bravo. eNeuro Jan 2016, 2 (2). DOI: 10.1523/ENEURO.0085-15.2016