scholarly journals Neural excitability increases with axonal resistance between soma and axon initial segment

2021 ◽  
Vol 118 (33) ◽  
pp. e2102217118
Author(s):  
Aurélie Fékété ◽  
Norbert Ankri ◽  
Romain Brette ◽  
Dominique Debanne
Keyword(s):  
Initial Segment ◽  
Compartmental Model ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Critical Role ◽  
Experimental Studies ◽  
Theoretical Work ◽  
Axon Initial Segment ◽  
Neural Excitability ◽  
Axial Resistance

The position of the axon initial segment (AIS) is thought to play a critical role in neuronal excitability. Previous experimental studies have found that a distal shift in AIS position correlates with a reduction in excitability. Yet theoretical work has suggested the opposite, because of increased electrical isolation. A distal shift in AIS position corresponds to an elevation of axial resistance Ra. We therefore examined how changes in Ra at the axon hillock impact the voltage threshold (Vth) of the somatic action potential in L5 pyramidal neurons. Increasing Ra by mechanically pinching the axon between the soma and the AIS was found to lower Vth by ∼6 mV. Conversely, decreasing Ra by substituting internal ions with higher mobility elevated Vth. All Ra-dependent changes in Vth could be reproduced in a Hodgkin–Huxley compartmental model. We conclude that in L5 pyramidal neurons, excitability increases with axial resistance and therefore with a distal shift of the AIS.

scholarly journals Neural excitability increases with axonal resistance between soma and axon initial segment

2020 ◽  
Author(s):  
Aurélie Fékété ◽  
Norbert Ankri ◽  
Romain Brette ◽  
Dominique Debanne
Keyword(s):  
Initial Segment ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Empirical Studies ◽  
Critical Role ◽  
Theoretical Work ◽  
Axon Initial Segment ◽  
Neural Excitability ◽  
Spike Threshold ◽  
Axial Resistance

AbstractThe position of the axon initial segment (AIS) is thought to play a critical role in neuronal excitability. In particular, empirical studies have found correlations between a distal shift in AIS position and a reduction of excitability. Yet, theoretical work has suggested that the neuron should become more excitable as the distance between soma and AIS is increased, because of increased electrical isolation. Specifically, resistive coupling theory predicts that the action potential (AP) threshold decreases with the logarithm of the axial resistance (Ra) between the middle of the AIS and the soma. However, no direct experimental evidence has been provided so far to support this theoretical prediction. We therefore examined how changes in Ra at the axon hillock impact the voltage threshold (Vth) of the somatic AP in L5 pyramidal neurons. Increasing Ra by mechanically pinching the axon between the soma and the AIS was found to lower the spike threshold by ~6 mV. Conversely, decreasing Ra by replacing a weakly mobile ion (gluconate) by a highly mobile ion (chloride) elevated the spike threshold. All Ra-dependent changes in spike threshold could be reproduced in a Hodgkin-Huxley compartmental model. We conclude that in L5 pyramidal neurons, excitability increases with axial resistance, and therefore with a distal shift of the AIS.

Control of Neuronal Output by Inhibition at the Axon Initial Segment

1990 ◽  
Vol 2 (3) ◽  
pp. 283-292 ◽  
Author(s):  
Rodney J. Douglas ◽  
Kevan A. C. Martin
Keyword(s):  
Visual Cortex ◽  
Action Potential ◽  
Initial Segment ◽  
Compartmental Model ◽  
Pyramidal Neurons ◽  
Axon Initial Segment ◽  
Synaptic Current ◽  
Basket Cells ◽  
Excitatory Synaptic Current ◽  
Neuronal Output

We examine the effect of inhibition on the axon initial segment (AIS) by the chandelier (“axoaxonic”) cells, using a simplified compartmental model of actual pyramidal neurons from cat visual cortex. We show that within generally accepted ranges, inhibition at the AIS cannot completely prevent action potential discharge: only small amounts of excitatory synaptic current can be inhibited. Moderate amounts of excitatory current always result in action potential discharge, despite AIS inhibition. Inhibition of the somadendrite by basket cells enhances the effect of AIS inhibition and vice versa. Thus the axoaxonic cells may act synergistically with basket cells: the AIS inhibition increases the threshold for action potential discharge, the basket cells then control the suprathreshold discharge.

scholarly journals M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment

2017 ◽  
Vol 114 (47) ◽  
pp. E10234-E10243 ◽  
Author(s):  
Jonathan Lezmy ◽  
Maya Lipinsky ◽  
Yana Khrapunsky ◽  
Eti Patrich ◽  
Lia Shalom ◽  
...  
Keyword(s):  
Initial Segment ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Primary Cultures ◽  
Axon Initial Segment ◽  
Channel Activity ◽  
Hippocampal Pyramidal Neurons ◽  
M Current ◽  
Ankyrin G ◽  
Trigger Zone

Alterations in synaptic input, persisting for hours to days, elicit homeostatic plastic changes in the axon initial segment (AIS), which is pivotal for spike generation. Here, in hippocampal pyramidal neurons of both primary cultures and slices, we triggered a unique form of AIS plasticity by selectively targeting M-type K+ channels, which predominantly localize to the AIS and are essential for tuning neuronal excitability. While acute M-current inhibition via cholinergic activation or direct channel block made neurons more excitable, minutes to hours of sustained M-current depression resulted in a gradual reduction in intrinsic excitability. Dual soma–axon patch-clamp recordings combined with axonal Na+ imaging and immunocytochemistry revealed that these compensatory alterations were associated with a distal shift of the spike trigger zone and distal relocation of FGF14, Na+, and Kv7 channels but not ankyrin G. The concomitant distal redistribution of FGF14 together with Nav and Kv7 segments along the AIS suggests that these channels relocate as a structural and functional unit. These fast homeostatic changes were independent of l-type Ca2+ channel activity but were contingent on the crucial AIS protein, protein kinase CK2. Using compartmental simulations, we examined the effects of varying the AIS position relative to the soma and found that AIS distal relocation of both Nav and Kv7 channels elicited a decrease in neuronal excitability. Thus, alterations in M-channel activity rapidly trigger unique AIS plasticity to stabilize network excitability.

scholarly journals Sensory input drives rapid homeostatic scaling of the axon initial segment in mouse barrel cortex

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nora Jamann ◽  
Dominik Dannehl ◽  
Nadja Lehmann ◽  
Robin Wagener ◽  
Corinna Thielemann ◽  
...  
Keyword(s):  
Action Potential ◽  
Initial Segment ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Barrel Cortex ◽  
Sensory Deprivation ◽  
Axon Initial Segment ◽  
Electrophysiological Recordings ◽  
Network States

AbstractThe axon initial segment (AIS) is a critical microdomain for action potential initiation and implicated in the regulation of neuronal excitability during activity-dependent plasticity. While structural AIS plasticity has been suggested to fine-tune neuronal activity when network states change, whether it acts in vivo as a homeostatic regulatory mechanism in behaviorally relevant contexts remains poorly understood. Using the mouse whisker-to-barrel pathway as a model system in combination with immunofluorescence, confocal analysis and electrophysiological recordings, we observed bidirectional AIS plasticity in cortical pyramidal neurons. Furthermore, we find that structural and functional AIS remodeling occurs in distinct temporal domains: Long-term sensory deprivation elicits an AIS length increase, accompanied with an increase in neuronal excitability, while sensory enrichment results in a rapid AIS shortening, accompanied by a decrease in action potential generation. Our findings highlight a central role of the AIS in the homeostatic regulation of neuronal input-output relations.

scholarly journals Optical measurement of physiological sodium currents in the axon initial segment

2020 ◽  
Author(s):  
Luiza Filipis ◽  
Marco Canepari
Keyword(s):  
Temporal Resolution ◽  
Initial Segment ◽  
Pyramidal Neurons ◽  
Optical Measurement ◽  
Brain Slices ◽  
Axon Initial Segment ◽  
Neuron Models ◽  
Pixel Resolution ◽  
Fluorescence Measurements ◽  
Kinetics Of

ABSTRACTIn most neurons of the mammalian central nervous system, the action potential (AP) is triggered in the axon initial segment (AIS) by a fast Na+ current mediated by voltage-gated Na+ channels. The intracellular Na+ increase associated with the AP has been measured using fluorescent Na+ indicators, but with insufficient resolution to resolve the Na+ current in the AIS. In this article, we report the critical improvement in temporal resolution of the Na+ imaging technique allowing the direct experimental measurement of Na+ currents in the AIS. We determined the AIS Na+ current, from fluorescence measurements at temporal resolution of 100 µs and pixel resolution of half a micron, in pyramidal neurons of the layer-5 of the somatosensory cortex from brain slices of the mouse. We identified a subthreshold current before the AP, a fast inactivating current peaking during the rise of the AP and a persistent current during the AP repolarisation. We correlated the kinetics of the current at different distances from the soma with the kinetics of the somatic AP. We quantitatively compared the experimentally measured Na+ current with the current obtained by computer simulation of published NEURON models and we show how the present approach can lead to the correct estimate of the native behaviour of Na+ channels. Thus, it is expected that the present method will be adopted to investigate the function of different channel types under physiological or pathological conditions.

scholarly journals Formin Activity and mDia1 Contribute to Maintain Axon Initial Segment Composition and Structure

2021 ◽  
Author(s):  
Wei Zhang ◽  
María Ciorraga ◽  
Pablo Mendez ◽  
Diana Retana ◽  
Norah Boumedine-Guignon ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Initial Segment ◽  
Protein Transport ◽  
Neuronal Excitability ◽  
Brain Slices ◽  
Axon Initial Segment ◽  
Composition And Structure ◽  
The Stability ◽  
Protein Density ◽  
Voltage Gated Ion Channels

AbstractThe axon initial segment (AIS) is essential for maintaining neuronal polarity, modulating protein transport into the axon, and action potential generation. These functions are supported by a distinctive actin and microtubule cytoskeleton that controls axonal trafficking and maintains a high density of voltage-gated ion channels linked by scaffold proteins to the AIS cytoskeleton. However, our knowledge of the mechanisms and proteins involved in AIS cytoskeleton regulation to maintain or modulate AIS structure is limited. In this context, formins play a significant role in the modulation of actin and microtubules. We show that pharmacological inhibition of formins modifies AIS actin and microtubule characteristics in cultured hippocampal neurons, reducing F-actin density and decreasing microtubule acetylation. Moreover, formin inhibition diminishes sodium channels, ankyrinG and βIV-spectrin AIS density, and AIS length, in cultured neurons and brain slices, accompanied by decreased neuronal excitability. We show that genetic downregulation of the mDia1 formin by interference RNAs also decreases AIS protein density and shortens AIS length. The ankyrinG decrease and AIS shortening observed in pharmacologically inhibited neurons and neuron-expressing mDia1 shRNAs were impaired by HDAC6 downregulation or EB1-GFP expression, known to increase microtubule acetylation or stability. However, actin stabilization only partially prevented AIS shortening without affecting AIS protein density loss. These results suggest that mDia1 maintain AIS composition and length contributing to the stability of AIS microtubules.

scholarly journals Of mice and intrinsic excitability: genetic background affects the size of the postburst afterhyperpolarization in CA1 pyramidal neurons

2011 ◽  
Vol 106 (3) ◽  
pp. 1570-1580 ◽  
Author(s):  
Shannon J. Moore ◽  
Benjamin T. Throesch ◽  
Geoffrey G. Murphy
Keyword(s):  
Genetic Background ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Critical Role ◽  
Genetically Engineered ◽  
Gradual Transition ◽  
Cellular Mechanisms ◽  
Ca1 Pyramidal Neurons ◽  
Genetically Engineered Mice ◽  
Cell Current

As the use of genetically engineered mice has become increasingly prevalent in neurobiological research, evidence has steadily accumulated that substantial differences exist between strains. Although a number of studies have reported effects of genetic background on behavior, few have focused on differences in neurophysiology. The postburst afterhyperpolarization (AHP) is an important determinant of intrinsic neuronal excitability and has been suggested to play a critical role in the cellular mechanisms underlying learning and memory. Using whole cell current-clamp recordings of CA1 pyramidal neurons, we examined the magnitude of different phases of the AHP (peak, medium, and slow) in two commonly used genetic backgrounds, C57BL/6 (B6) and 129SvEv (129), as well as in an F2 hybrid B6:129 background (F2). We found that neurons from B6 and F2 animals exhibited a significantly larger AHP compared with 129 animals and that this difference was consistent across all phases. Furthermore, our recordings revealed a marked dichotomy in the shape of the AHP waveform, which was independent of genetic background. Approximately 60% of cells exhibited an AHP with a sharp transition between the peak AHP and medium AHP, whereas the remaining 40% exhibited a more gradual transition. Our data add to the growing body of work suggesting that genetic background can affect neuronal function as well as behavior. In addition, these results highlight the innate heterogeneity of CA1 pyramidal neurons, even within a single genetic background. These differences should be taken into consideration during the analysis and comparison of experimental results.

scholarly journals COUP-TFI regulates diameter of the axon initial segment in the mammalian neocortex

2020 ◽  
Author(s):  
Xuanyuan Wu ◽  
Haixiang Li ◽  
Jiechang Huang ◽  
Cheng Xiao ◽  
Shuijin He
Keyword(s):  
Action Potential ◽  
Initial Segment ◽  
Neuronal Excitability ◽  
Developmental Stages ◽  
Pyramidal Cells ◽  
Axon Initial Segment ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Cell Ablation ◽  
Specialized Structure

AbstractThe axon initial segment is a specialized structure that controls neuronal excitability by generating action potentials. Currently, AIS plasticity with regard to changes in length and location in response to neural activity has been extensively investigated, but how AIS diameter is regulated remains elusive. Here we report that COUP-TFI is an essential regulator of AIS diameter in both developing and adult mouse neocortex. Embryonic ablation of COUP-TFI prevented expansion of AIS diameter that occurs during postnatal development in layer II/III pyramidal cells of the mouse motor cortex, thereby leading to an impairment of action potential generation. Inactivation of COUP-TFI in adult neurons also led to reduced AIS diameter and impaired action potential generation. In contrast to different developmental stages, single-cell ablation and global ablation produced opposite effects on spontaneous network in COUP-TFI-deficient neurons. Further, mice exhibited less anxiety-like behaviors after postnatal inactivation of COUP-TFI induced by tamoxifen. Our results demonstrate that COUP-TFI is indispensable for both expansion and maintenance of AIS diameter and that a change in AIS diameter fine-tunes synaptic inputs through a metaplasticity mechanism in the adult neocortex.

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