scholarly journals ADAM22 and ADAM23 modulate the targeting of the Kv1 channel-associated protein LGI1 to the axon initial segment

2018 ◽  
Author(s):  
Bruno Hivert ◽  
Laurène Marien ◽  
Komlan Nassirou Agbam ◽  
Catherine Faivre-Sarrailh
Keyword(s):  
Hippocampal Neurons ◽  
Live Cell Imaging ◽  
Initial Segment ◽  
Cell Imaging ◽  
Autosomal Dominant ◽  
Neurological Diseases ◽  
Axon Initial Segment ◽  
Intrinsic Excitability ◽  
Missense Mutant ◽  
Combinatorial Expression

AbstractThe distribution of voltage-gated potassium channels Kv1 at the axon initial segment (AIS), along the axon and at presynaptic terminals influences intrinsic excitability and transmitter release. Kv1.1/1.2 subunits are associated with cell adhesion molecules (CAMs), including Caspr2 and LGI1 that are implicated in autoimmune and genetic neurological diseases with seizures. In particular, mutations in the LGI1 gene cause autosomal dominant lateral temporal lobe epilepsy (ADTLE). In the present study, we used rat hippocampal neurons in culture to assess whether interplay between distinct Kv1-associated CAMs contributes to targeting at the AIS. Strikingly, LGI1 was highly restricted to the AIS surface when transfected alone, whereas the missense mutant LGI1S473L associated with ADLTE was not. Next, we showed that ADAM22 and ADAM23 acted as chaperones to promote axonal vesicular transport of LGI1 reducing its density at the AIS. Moreover, live-cell imaging of fluorescently labelled CAMs indicated that LGI1 was co-transported in axonal vesicles with ADAM22 or ADAM23. Finally, we showed that ADAM22 and ADAM23 also associate with Caspr2 and TAG-1 to be selectively targeted within different axonal sub-regions. The combinatorial expression of Kv1-associated CAMs may be critical to tune intrinsic excitability in a physiological or an epileptogenic context.

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 Tropomyosin Tpm3.1 is required to maintain the structure and function of the axon initial segment

2019 ◽  
Author(s):  
Amr Abouelezz ◽  
Holly Stefen ◽  
Mikael Segerstråle ◽  
David Micinski ◽  
Rimante Minkeviciene ◽  
...  
Keyword(s):  
Actin Filaments ◽  
Hippocampal Neurons ◽  
Initial Segment ◽  
Actin Polymerization ◽  
Firing Frequency ◽  
Axon Initial Segment ◽  
Action Potential Initiation ◽  
Sodium Ion Channels ◽  
And Function ◽  
Filament Network

ABSTRACTThe axon initial segment (AIS) is the site of action potential initiation and serves as a vesicular filter and diffusion barrier that help maintain neuronal polarity. Recent studies have revealed details about a specialized structural complex in the AIS. While an intact actin cytoskeleton is required for AIS formation, pharmacological disruption of actin polymerization compromises the AIS vesicle filter but does not affect overall AIS structure. In this study, we found that the tropomyosin isoform Tpm3.1 decorates a population of relatively stable actin filaments in the AIS. Inhibiting Tpm3.1 in cultured hippocampal neurons led to the loss of AIS structure, the AIS vesicle filter, the clustering of sodium ion channels, and reduced firing frequency. We propose that Tpm3.1-decorated actin filaments form a stable actin filament network under the AIS membrane which provides a scaffold for membrane organization and AIS proteins.

Activity-dependent release of tissue plasminogen activator from the dendritic spines of hippocampal neurons revealed by live-cell imaging

2006 ◽  
Vol 66 (6) ◽  
pp. 564-577 ◽  
Author(s):  
Janis E. Lochner ◽  
Leah S. Honigman ◽  
Wilmon F. Grant ◽  
Sarah K. Gessford ◽  
Alexis B. Hansen ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Live Cell ◽  
Tissue Plasminogen ◽  
Activity Dependent

The Fate of Nascent APP in Hippocampal Neurons: A Live Cell Imaging Study

2018 ◽  
Vol 9 (9) ◽  
pp. 2225-2232
Author(s):  
Claire E. DelBove ◽  
Xian-zhen Deng ◽  
Qi Zhang
Keyword(s):  
Hippocampal Neurons ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Imaging Study ◽  
Live Cell

scholarly journals The Cell Adhesion Molecule Neurofascin Stabilizes Axo-axonic GABAergic Terminals at the Axon Initial Segment

2011 ◽  
Vol 286 (27) ◽  
pp. 24385-24393 ◽  
Author(s):  
Martin Kriebel ◽  
Jennifer Metzger ◽  
Sabine Trinks ◽  
Deepti Chugh ◽  
Robert J. Harvey ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Hippocampal Neurons ◽  
Initial Segment ◽  
Cell Adhesion Molecule ◽  
Synapse Formation ◽  
Growth Factor Receptor ◽  
Axon Initial Segment ◽  
Adult Rat ◽  
Receptor Clusters

Cell adhesion molecules regulate synapse formation and maintenance via transsynaptic contact stabilization involving both extracellular interactions and intracellular postsynaptic scaffold assembly. The cell adhesion molecule neurofascin is localized at the axon initial segment of granular cells in rat dentate gyrus, which is mainly targeted by chandelier cells. Lentiviral shRNA-mediated knockdown of neurofascin in adult rat brain indicates that neurofascin regulates the number and size of postsynaptic gephyrin scaffolds, the number of GABAA receptor clusters as well as presynaptic glutamate decarboxylase-positive terminals at the axon initial segment. By contrast, overexpression of neurofascin in hippocampal neurons increases gephyrin cluster size presumably via stimulation of fibroblast growth factor receptor 1 signaling pathways.

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.

scholarly journals The palmitoyl acyltransferase ZDHHC14 controls Kv1-family potassium channel clustering at the axon initial segment

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Shaun S Sanders ◽  
Luiselys M Hernandez ◽  
Heun Soh ◽  
Santi Karnam ◽  
Randall S Walikonis ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Initial Segment ◽  
Neuronal Excitability ◽  
Pdz Domain ◽  
Axon Initial Segment ◽  
Type I ◽  
Action Potential Firing ◽  
Outward Currents ◽  
Potential Firing ◽  
Palmitoyl Acyltransferase

The 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.

scholarly journals Developmental Expression of Kv Potassium Channels at the Axon Initial Segment of Cultured Hippocampal Neurons

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e48557 ◽  
Author(s):  
Diana Sánchez-Ponce ◽  
Javier DeFelipe ◽  
Juan José Garrido ◽  
Alberto Muñoz
Keyword(s):  
Potassium Channels ◽  
Hippocampal Neurons ◽  
Initial Segment ◽  
Axon Initial Segment ◽  
Developmental Expression ◽  
Cultured Hippocampal Neurons

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.

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