scholarly journals Somatic Proximity of the Axon Initial Segment Predicts Motoneuron Excitability

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.

scholarly journals Axon initial segment geometry in relation to motoneuron excitability

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259918
Author(s):  
Travis M. Rotterman ◽  
Darío I. Carrasco ◽  
Stephen N. Housley ◽  
Paul Nardelli ◽  
Randall K. Powers ◽  
...  
Keyword(s):  
Initial Segment ◽  
Neuronal Excitability ◽  
Causal Relation ◽  
Dynamic Structure ◽  
Motor Units ◽  
Axon Initial Segment ◽  
Medial Gastrocnemius ◽  
Intrinsic Excitability ◽  
Relationship Of

The axon initial segment (AIS) responsible for action potential initiation is a dynamic structure that varies and changes together with neuronal excitability. Like other neuron types, alpha motoneurons in the mammalian spinal cord express heterogeneity and plasticity in AIS geometry, including length (AISl) and distance from soma (AISd). The present study aimed to establish the relationship of AIS geometry with a measure of intrinsic excitability, rheobase current, that varies by 20-fold or more among normal motoneurons. 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 greater than that for motoneurons from the soleus (SOL) motor pool, which is more readily recruited in low-level activities. Next, we tested whether AISd covaried with intrinsic excitability of individual motoneurons. In anesthetized rats, we measured rheobase current intracellularly from MG motoneurons in vivo before labeling them for immunohistochemical study of AIS structure. For 16 motoneurons sampled from the MG motor pool, this combinatory approach revealed that AISd, but not AISl, was significantly related to rheobase, as AIS tended to be located further from the soma on motoneurons that were less excitable. Although a causal relation with excitability seems unlikely, AISd falls among a constellation of properties related to the recruitability of motor units and their parent motoneurons.

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

2020 ◽  
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.

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 Rem2 stabilizes intrinsic excitability and spontaneous firing in visual circuits

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Anna R Moore ◽  
Sarah E Richards ◽  
Katelyn Kenny ◽  
Leandro Royer ◽  
Urann Chan ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Ocular Dominance ◽  
Sensory Experience ◽  
Cellular Level ◽  
Synaptic Function ◽  
Intrinsic Excitability ◽  
Spontaneous Firing ◽  
Circuit Function

Sensory experience plays an important role in shaping neural circuitry by affecting the synaptic connectivity and intrinsic properties of individual neurons. Identifying the molecular players responsible for converting external stimuli into altered neuronal output remains a crucial step in understanding experience-dependent plasticity and circuit function. Here, we investigate the role of the activity-regulated, non-canonical Ras-like GTPase Rem2 in visual circuit plasticity. We demonstrate that Rem2-/- mice fail to exhibit normal ocular dominance plasticity during the critical period. At the cellular level, our data establish a cell-autonomous role for Rem2 in regulating intrinsic excitability of layer 2/3 pyramidal neurons, prior to changes in synaptic function. Consistent with these findings, both in vitro and in vivo recordings reveal increased spontaneous firing rates in the absence of Rem2. Taken together, our data demonstrate that Rem2 is a key molecule that regulates neuronal excitability and circuit function in the context of changing sensory experience.

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 Homeostatic plasticity rules control the wiring of axo-axonic synapses at the axon initial segment

2018 ◽  
Author(s):  
Alejandro Pan-Vazquez ◽  
Winnie Wefelmeyer ◽  
Victoria Gonzalez Sabater ◽  
Juan Burrone
Keyword(s):  
Initial Segment ◽  
Pyramidal Cells ◽  
Axon Initial Segment ◽  
Homeostatic Plasticity ◽  
Network Activity ◽  
Gabaergic Interneuron ◽  
Chandelier Cells ◽  
Local Circuits ◽  
And Function

AbstractGABAergic interneurons are chiefly responsible for controlling the activity of local circuits in the cortex1,2. However, the rules that govern the wiring of interneurons are not well understood3. Chandelier cells (ChCs) are a type of GABAergic interneuron that control the output of hundreds of neighbouring pyramidal cells through axo-axonic synapses which target the axon initial segment (AIS)4. Despite their importance in modulating circuit activity, our knowledge of the development and function of axo-axonic synapses remains elusive. In this study, we investigated the role of activity in the formation and plasticity of ChC synapses. In vivo imaging of ChCs during development uncovered a narrow window (P12-P18) over which axons arborized and formed connections. We found that increases in the activity of either pyramidal cells or individual ChCs during this temporal window resulted in a reversible decrease in axo-axonic connections. Voltage imaging of GABAergic transmission at the AIS showed that axo-axonic synapses were depolarising during this period. Identical manipulations of network activity in older mice (P40-P46), when ChC synapses are inhibitory, resulted in an increase in axo-axonic synapses. We propose that the direction of ChC plasticity follows homeostatic rules that depend on the polarity of axo-axonic synapses.

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.

scholarly journals Contribution of the axon initial segment to action potentials recorded extracellularly

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.

scholarly journals The Palmitoyl Acyltransferase ZDHHC14 Controls Kv1-Family Potassium Channel Clustering at the Axon Initial Segment

2020 ◽  
Author(s):  
Shaun S. Sanders ◽  
Luiselys M. Hernandez ◽  
Heun Soh ◽  
Santi Karnam ◽  
Randall S. Walikonis ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Hippocampal Neurons ◽  
Initial Segment ◽  
Neuronal Excitability ◽  
Pdz Domain ◽  
Axon Initial Segment ◽  
Type I ◽  
Action Potential Firing ◽  
Potential Firing ◽  
Palmitoyl Acyltransferase

AbstractThe palmitoyl acyltransferase (PAT) ZDHHC14 is highly expressed in the hippocampus and is the only PAT predicted to bind Type I PDZ domain-containing proteins. However, ZDHHC14’s neuronal roles are unknown. Here, we identify the PDZ domain-containing Membrane-associated Guanylate Kinase (MaGUK) PSD93 as a direct ZDHHC14 interactor and substrate. PSD93, but not other MaGUKs, localizes to the Axon Initial Segment (AIS). Using lentiviral-mediated shRNA knockdown in rat hippocampal neurons, we find that ZDHHC14 controls palmitoylation and AIS clustering of PSD93 and also of Kv1 potassium channels, which directly bind PSD93. Neurodevelopmental expression of ZDHHC14 mirrors that of PSD93 and Kv1 channels and, consistent with ZDHHC14’s importance for Kv1 channel clustering, loss of ZDHHC14 decreases outward currents and increases action potential firing in hippocampal neurons. To our knowledge, these findings identify the first neuronal roles and substrates for ZDHHC14 and reveal a previously unappreciated role for palmitoylation in control of neuronal excitability.Impact StatementZDHHC14 controls palmitoylation and axon initial segment targeting of PSD93 and Kv1-family potassium channels, events that are essential for normal neuronal excitability.

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