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

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.

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

10.1101/2020.02.27.968065 ◽

2020 ◽

Cited By ~ 1

Author(s):

Nora Jamann ◽

Dominik Dannehl ◽

Robin Wagener ◽

Corinna Corcelli ◽

Christian Schultz ◽

...

Keyword(s):

Action Potential ◽

Initial Segment ◽

Neuronal Excitability ◽

Barrel Cortex ◽

Cortical Plasticity ◽

Sensory Deprivation ◽

Axon Initial Segment ◽

Electrophysiological Recordings ◽

Network States

SummaryThe axon initial segment (AIS) is an important axonal microdomain for action potential initiation and implicated in the regulation of neuronal excitability during activity-dependent cortical plasticity. While structural AIS plasticity has been suggested to fine-tune neuronal activity when network states change, whether it acts as a homeostatic regulatory mechanism in behaviorally relevant contexts remains poorly understood. Using an in vivo model of the mouse whisker-to-barrel pathway in combination with immunofluorescence, confocal analysis and patch-clamp electrophysiological recordings, we observed bidirectional AIS plasticity. 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.

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Control of Neuronal Output by Inhibition at the Axon Initial Segment

Neural Computation ◽

10.1162/neco.1990.2.3.283 ◽

1990 ◽

Vol 2 (3) ◽

pp. 283-292 ◽

Cited By ~ 31

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.

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

10.1101/2020.10.07.329284 ◽

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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Functional microstructure of CaV-mediated calcium signaling in the axon initial segment

10.1101/2020.11.13.382374 ◽

2020 ◽

Author(s):

Anna M Lipkin ◽

Margaret M Cunniff ◽

Perry WE Spratt ◽

Stefan M Lemke ◽

Kevin J Bender

Keyword(s):

Calcium Channels ◽

Action Potential ◽

High Speed ◽

Initial Segment ◽

Laser Scanning ◽

Pyramidal Neurons ◽

Calcium Influx ◽

Axon Initial Segment ◽

Spatiotemporal Resolution ◽

Sodium Potassium

ABSTRACTThe axon initial segment (AIS) is a specialized neuronal compartment in which synaptic input is converted into action potential output. This process is supported by a diverse complement of sodium, potassium, and calcium channels (CaV). Different classes of sodium and potassium channels are scaffolded at specific sites within the AIS, conferring unique functions, but how calcium channels are functionally distributed within the AIS is unclear. Here, we utilize conventional 2-photon laser scanning and diffraction-limited, high-speed spot 2-photon imaging to resolve action potential-evoked calcium dynamics in the AIS with high spatiotemporal resolution. In mouse layer 5 prefrontal pyramidal neurons, calcium influx was mediated by a mix of CaV2 and CaV3 channels that differentially localized to discrete regions. CaV3 functionally localized to produce nanodomain hotspots of calcium influx that coupled to ryanodine-dependent stores, whereas CaV2 localized to non-hotspot regions. Thus, different pools of CaVs appear to play distinct roles in AIS function.

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Contribution of the axon initial segment to action potentials recorded extracellularly

10.1101/243808 ◽

2018 ◽

Author(s):

Maria Teleńczuk ◽

Romain Brette ◽

Alain Destexhe ◽

Bartosz Teleńczuk

Keyword(s):

Action Potential ◽

Electric Fields ◽

Action Potentials ◽

Initial Segment ◽

Initiation Site ◽

Axon Initial Segment ◽

Neuron Activity ◽

Classical Models ◽

The Brain

AbstractAction potentials (APs) are electric phenomena that are recorded both intracellularly and extracellularly. APs are usually initiated in the short segment of the axon called the axon initial segment (AIS). It was recently proposed that at onset of an AP the soma and the AIS form a dipole. We study the extracellular signature (the extracellular action potential, EAP) generated by such a dipole. First, we demonstrate the formation of the dipole and its extracellular signature in detailed morphological models of a reconstructed pyramidal neuron. Then, we study the EAP waveform and its spatial dependence in models with axonal AP initiation and contrast it with the EAP obtained in models with somatic AP initiation. We show that in the models with axonal AP initiation the dipole forms between somatodendritic compartments and the AIS, and not between soma and dendrites as in the classical models. Soma-dendrites dipole is present only in models with somatic AP initiation. Our study has consequences for interpreting extracellular recordings of single-neuron activity and determining electrophysiological neuron types, but also for better understanding the origins of the high-frequency macroscopic electric fields recorded in the brain.New & NoteworthyWe studied the consequences of the action potential (AP) initiation site on the extracellular signatures of APs. We show that: (1) at the time of AP initiation the action initial segment (AIS) forms a dipole with the soma, (2) the width but not (3) amplitude of the extracellular AP generated by this dipole increases with the soma-AIS distance. This may help to monitor dynamic changes in the AIS position in experimental in vivo recordings.

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Covariation of axon initial segment location and dendritic tree normalizes the somatic action potential

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1607548113 ◽

2016 ◽

Vol 113 (51) ◽

pp. 14841-14846 ◽

Cited By ~ 41

Author(s):

Mustafa S. Hamada ◽

Sarah Goethals ◽

Sharon I. de Vries ◽

Romain Brette ◽

Maarten H. P. Kole

Keyword(s):

Action Potential ◽

Initial Segment ◽

Pyramidal Neurons ◽

Dendritic Tree ◽

Apical Dendrite ◽

Axial Current ◽

Axon Initial Segment ◽

Output Code ◽

The Face ◽

Dendritic Complexity

In mammalian neurons, the axon initial segment (AIS) electrically connects the somatodendritic compartment with the axon and converts the incoming synaptic voltage changes into a temporally precise action potential (AP) output code. Although axons often emanate directly from the soma, they may also originate more distally from a dendrite, the implications of which are not well-understood. Here, we show that one-third of the thick-tufted layer 5 pyramidal neurons have an axon originating from a dendrite and are characterized by a reduced dendritic complexity and thinner main apical dendrite. Unexpectedly, the rising phase of somatic APs is electrically indistinguishable between neurons with a somatic or a dendritic axon origin. Cable analysis of the neurons indicated that the axonal axial current is inversely proportional to the AIS distance, denoting the path length between the soma and the start of the AIS, and to produce invariant somatic APs, it must scale with the local somatodendritic capacitance. In agreement, AIS distance inversely correlates with the apical dendrite diameter, and model simulations confirmed that the covariation suffices to normalize the somatic AP waveform. Therefore, in pyramidal neurons, the AIS location is finely tuned with the somatodendritic capacitive load, serving as a homeostatic regulation of the somatic AP in the face of diverse neuronal morphologies.

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Somatic Proximity of the Axon Initial Segment Predicts Motoneuron Excitability

10.21203/rs.3.rs-318156/v1 ◽

2021 ◽

Author(s):

Travis M Rotterman ◽

Dario Carrasco ◽

Nick Housley ◽

Paul Nardelli ◽

Randy K Powers ◽

...

Keyword(s):

Initial Segment ◽

Neuronal Excitability ◽

Structural Parameters ◽

Axon Initial Segment ◽

Medial Gastrocnemius ◽

Intrinsic Excitability ◽

Spinal Motoneurons ◽

Motoneuron Excitability ◽

Gated Channel

Abstract As the neuronal site where voltage gated channel density is highest, the axon initial segment (AIS) plays a key role in establishing a neuron’s action potential threshold, i.e. excitability. Among the properties of AIS that gain attention are length (AISl) and distance from the soma (AISd), which are variously found to change together with neuronal excitability following experimentally-induced perturbations in neural activity. The present study was designed to test the possibility that variation in AIS structural parameters regulates the native range in intrinsic excitability for one class of mature neurons. Spinal motoneurons were selected for their naturally large range in excitability and for their experimental accessibility to in vivo study. We began by determining whether AIS length or distance differed for motoneurons in motor pools that exhibit different activity profiles. Motoneurons sampled from the medial gastrocnemius (MG) motor pool exhibited values for average AISd that were significantly more than for motoneurons from the soleus (SOL) motor pool, which is more readily activated in low-level movements. Next, we tested whether AISd covaried with intrinsic excitability of individual motoneurons. Using anesthetized rats, we measured rheobase current intracellularly from MG motoneurons before labeling them for later immunohistochemical study of AIS. This combinatory approach revealed a significant correlation between AISd and rheobase, for 16 motoneurons sampled within the MG motor pool. Among multiple electrophysiological and morphological parameters measured here, AISd stood out as the dominant predictor of motoneuron excitability. These findings suggest an important role for AISd in setting the intrinsic excitability of spinal motoneurons.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1708700114 ◽

2017 ◽

Vol 114 (47) ◽

pp. E10234-E10243 ◽

Cited By ~ 23

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.

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Activity-dependent mismatch between axo-axonic synapses and the axon initial segment controls neuronal output

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1502902112 ◽

2015 ◽

Vol 112 (31) ◽

pp. 9757-9762 ◽

Cited By ~ 52

Author(s):

Winnie Wefelmeyer ◽

Daniel Cattaert ◽

Juan Burrone

Keyword(s):

Action Potential ◽

Hippocampal Neurons ◽

Initial Segment ◽

Pyramidal Neurons ◽

Neuronal Cell ◽

Axon Initial Segment ◽

Action Potential Generation ◽

Potential Generation ◽

Auditory Nucleus

The axon initial segment (AIS) is a structure at the start of the axon with a high density of sodium and potassium channels that defines the site of action potential generation. It has recently been shown that this structure is plastic and can change its position along the axon, as well as its length, in a homeostatic manner. Chronic activity-deprivation paradigms in a chick auditory nucleus lead to a lengthening of the AIS and an increase in neuronal excitability. On the other hand, a long-term increase in activity in dissociated rat hippocampal neurons results in an outward movement of the AIS and a decrease in the cell’s excitability. Here, we investigated whether the AIS is capable of undergoing structural plasticity in rat hippocampal organotypic slices, which retain the diversity of neuronal cell types present at postnatal ages, including chandelier cells. These interneurons exclusively target the AIS of pyramidal neurons and form rows of presynaptic boutons along them. Stimulating individual CA1 pyramidal neurons that express channelrhodopsin-2 for 48 h leads to an outward shift of the AIS. Intriguingly, both the pre- and postsynaptic components of the axo-axonic synapses did not change position after AIS relocation. We used computational modeling to explore the functional consequences of this partial mismatch and found that it allows the GABAergic synapses to strongly oppose action potential generation, and thus downregulate pyramidal cell excitability. We propose that this spatial arrangement is the optimal configuration for a homeostatic response to long-term stimulation.

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