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Yilin Tai, Nicholas B Gallo, Minghui Wang, Jia-Ray Yu, Linda Van Aelst
Among the diverse interneuron subtypes in the neocortex, chandelier cells (ChCs) are the only population that selectively innervate pyramidal neurons (PyNs) at their axon initial segment (AIS), the site of action potential initiation, allowing them to exert powerful control over PyN output. Yet, mechanisms underlying their subcellular innervation of PyN AISs are unknown. To identify molecular determinants of ChC/PyN AIS innervation, we performed an in vivo RNAi screen of PyN-expressed axonal cell adhesion molecules (CAMs) and select Ephs/ephrins...
February 21, 2019: Neuron
Scott A Alpizar, Arielle L Baker, Allan T Gulledge, Michael B Hoppa
The axon initial segment (AIS) is a specialized region within the proximal portion of the axon that initiates action potentials thanks in large part to an enrichment of sodium channels. The scaffolding protein ankyrinG (AnkG) is essential for the recruitment of sodium channels as well as several other intracellular and extracellular proteins to the AIS. In the present study, we explore the role of the cell adhesion molecule (CAM) neurofascin-186 (NF-186) in arranging the individual molecular components of the AIS in cultured rat hippocampal neurons...
2019: Frontiers in Cellular Neuroscience
Chih-Chuan Wang, Xilma R Ortiz-González, Sabrina W Yum, Sara M Gill, Amy White, Erin Kelter, Laurie H Seaver, Sansan Lee, Graham Wiley, Patrick M Gaffney, Klaas J Wierenga, Matthew N Rasband
βIV spectrin links ankyrinG (AnkG) and clustered ion channels at axon initial segments (AISs) and nodes of Ranvier to the axonal cytoskeleton. Here, we report bi-allelic pathogenic SPTBN4 variants (three homozygous and two compound heterozygous) that cause a severe neurological syndrome that includes congenital hypotonia, intellectual disability, and motor axonal and auditory neuropathy. We introduced these variants into βIV spectrin, expressed these in neurons, and found that 5/7 were loss-of-function variants disrupting AIS localization or abolishing phosphoinositide binding...
June 7, 2018: American Journal of Human Genetics
Yuki Ogawa, Junji Yamaguchi, Masato Yano, Yasuo Uchiyama, Hirotaka James Okano
Alternative splicing of RNAs diversifies the functionalities of proteins, and it is optimized for each cell type and each developmental stage. nElavl (composed of Elavl2, Elavl3, and Elavl4) proteins are the RNA-binding proteins that is specifically expressed in neurons, regulate the alternative splicing of target RNAs, and promote neuronal differentiation and maturation. Recent studies revealed that Elavl3 knockout (Elavl3-/- ) mice completely lost the expression of nElavl proteins in the Purkinje cells and exhibited cerebellar dysfunction...
October 2018: Neuroscience Research
Tian-Tian Liu, Li Feng, Heng-Fang Liu, Yi Shu, Bo Xiao
Hippocampal neurogenesis in temporal lobe epilepsy (TLE) may result in alteration of the excitability of neurons, which contributes to spontaneous recurrent seizures. Axon initial segment (AIS) structural and functional plasticity is important in the control of neuronal excitability. It remains to be elucidated whether the plasticity of AIS occurs in hippocampal newly‑generated neurons that are involved in recurrent seizures following pilocarpine‑induced status epilepticus (SE). The present study first established a pilocarpine‑induced TLE rat model to assess the features of newborn neurons and AIS plasticity alterations using double immunofluorescence staining of Ankyrin G and doublecortin (DCX)...
September 2017: Molecular Medicine Reports
Benjamin Yang, Bridget M Curran, Stephen R Tymanskyj
No abstract text is available yet for this article.
June 14, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
I M van der Werf, D Van Dam, S Missault, B Yalcin, P P De Deyn, G Vandeweyer, R F Kooy
ANK3 encodes AnkyrinG (AnkG), a member of the Ankyrin family that is expressed in several different isoforms in many tissues. A unique serine-rich domain and tail domain in the two largest isoforms of AnkG (270 and 480kDa), restrict AnkG to the axon initial segment and nodes of Ranvier of myelinated neurons. At these sites, AnkG is a master regulator, coordinating the strict clustering of components necessary for proper action potential initiation and propagation along the axon. These components include voltage-gated sodium channels, potassium channels and members of the L1 cell adhesion molecule family...
June 15, 2017: Behavioural Brain Research
Mónica Tapia, Ana Dominguez, Wei Zhang, Ana Del Puerto, María Ciorraga, María José Benitez, Carmen Guaza, Juan José Garrido
Neuronal polarization underlies the ability of neurons to integrate and transmit information. This process begins early in development with axon outgrowth, followed by dendritic growth and subsequent maturation. In between these two steps, the axon initial segment (AIS), a subcellular domain crucial for generating action potentials (APs) and maintaining the morphological and functional polarization, starts to develop. However, the cellular/molecular mechanisms and receptors involved in AIS initial development and maturation are mostly unknown...
2017: Frontiers in Cellular Neuroscience
Takeshi Yoshimura, Sharon R Stevens, Cristophe Leterrier, Michael C Stankewich, Matthew N Rasband
Axon initial segments (AIS) and nodes of Ranvier are highly specialized axonal membrane domains enriched in Na(+) channels. These Na(+) channel clusters play essential roles in action potential initiation and propagation. AIS and nodal Na(+) channel complexes are linked to the actin cytoskeleton through βIV spectrin. However, neuronal βIV spectrin exists as two main splice variants: a longer βIVΣ1 variant with canonical N-terminal actin and αII spectrin-binding domains, and a shorter βIVΣ6 variant lacking these domains...
2016: Frontiers in Cellular Neuroscience
Jie Xu, Emmanuelle Berret, Jun Hee Kim
In auditory pathways, the precision of action potential (AP) propagation depends on axon myelination and high densities of voltage-gated Na (Nav ) channels clustered at nodes of Ranvier. Changes in Nav channel expression at the heminode, the final node before the nerve terminal, can alter AP invasion into the presynaptic terminal. We studied the activity-dependent formation of Nav channel clusters before and after hearing onset at postnatal day 12 in the rat and mouse auditory brain stem. In rats, the Nav channel cluster at the heminode formed progressively during the second postnatal week, around hearing onset, whereas the Nav channel cluster at the nodes was present before hearing onset...
February 1, 2017: Journal of Neurophysiology
Miguel A Marin, Silmara de Lima, Hui-Ya Gilbert, Roman J Giger, Larry Benowitz, Matthew N Rasband
UNLABELLED: Action potential initiation and propagation in myelinated axons require ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Disruption of these domains after injury impairs nervous system function. Traditionally, injured CNS axons are considered refractory to regeneration, but some recent approaches challenge this view by showing robust long-distance regeneration. However, whether these approaches allow remyelination and promote the reestablishment of AIS and nodes of Ranvier is unknown...
August 31, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Yuichiro Fujiwara, Hiroko X Kondo, Matsuyuki Shirota, Megumi Kobayashi, Kohei Takeshita, Atsushi Nakagawa, Yasushi Okamura, Kengo Kinoshita
By clustering various ion channels and transporters, ankyrin-G (AnkG) configures the membrane-excitation platforms in neurons and cardiomyocytes. AnkG itself localizes to specific areas on the plasma membrane via s-palmitoylation of Cys. However, the structural mechanism by which AnkG anchors to the membrane is not understood. In this study, we solved the crystal structures of the reduced and oxidized forms of the AnkG s-palmitoylation domain and used multiple long-term coarse-grained molecular dynamics simulations to analyze their membrane association...
April 5, 2016: Scientific Reports
Christopher Patzke, Claudio Acuna, Louise R Giam, Marius Wernig, Thomas C Südhof
Hundreds of L1CAM gene mutations have been shown to be associated with congenital hydrocephalus, severe intellectual disability, aphasia, and motor symptoms. How such mutations impair neuronal function, however, remains unclear. Here, we generated human embryonic stem (ES) cells carrying a conditional L1CAM loss-of-function mutation and produced precisely matching control and L1CAM-deficient neurons from these ES cells. In analyzing two independent conditionally mutant ES cell clones, we found that deletion of L1CAM dramatically impaired axonal elongation and, to a lesser extent, dendritic arborization...
April 4, 2016: Journal of Experimental Medicine
Elizabeth J Akin, Laura Solé, Sulayman D Dib-Hajj, Stephen G Waxman, Michael M Tamkun
During axonal maturation, voltage-gated sodium (Nav) channels accumulate at the axon initial segment (AIS) at high concentrations. This localization is necessary for the efficient initiation of action potentials. The mechanisms underlying channel trafficking to the AIS during axonal development have remained elusive due to a lack of Nav reagents suitable for high resolution imaging of channels located specifically on the cell surface. Using an optical pulse-chase approach in combination with a novel Nav1.6 construct containing an extracellular biotinylation domain we demonstrate that Nav1...
2015: PloS One
Kelli Baalman, Miguel A Marin, Tammy Szu-Yu Ho, Marlesa Godoy, Leela Cherian, Claudia Robertson, Matthew N Rasband
Microglia are the brain's resident immune cells and function as the main defense against pathogens or injury. However, in the absence of disease, microglia have other functions in the normal brain. For example, previous studies showed that microglia contribute to circuit refinement and synaptic plasticity in the developing and adult brain, respectively. Thus, microglia actively participate in regulating neuronal excitability and function. Here, we report that in the cortex, but not other brain regions, a subset of microglia extend a single process that specifically associates and overlaps with the axon initial segment (AIS), the site where action potentials are generated...
February 4, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Sean A Freeman, Anne Desmazières, Jean Simonnet, Marie Gatta, Friederike Pfeiffer, Marie Stéphane Aigrot, Quentin Rappeneau, Serge Guerreiro, Patrick Pierre Michel, Yuchio Yanagawa, Gilles Barbin, Peter J Brophy, Desdemona Fricker, Catherine Lubetzki, Nathalie Sol-Foulon
High-density accumulation of voltage-gated sodium (Nav) channels at nodes of Ranvier ensures rapid saltatory conduction along myelinated axons. To gain insight into mechanisms of node assembly in the CNS, we focused on early steps of nodal protein clustering. We show in hippocampal cultures that prenodes (i.e., clusters of Nav channels colocalizing with the scaffold protein ankyrinG and nodal cell adhesion molecules) are detected before myelin deposition along axons. These clusters can be induced on purified neurons by addition of oligodendroglial-secreted factor(s), whereas ankyrinG silencing prevents their formation...
January 20, 2015: Proceedings of the National Academy of Sciences of the United States of America
Takeshi Yoshimura, Matthew N Rasband
The axon initial segment (AIS) is a structurally and molecularly unique neuronal compartment of the proximal axon that functions as both a physiological and physical bridge between the somatodendritic and axonal domains. The AIS has two main functions: to initiate action potentials and to maintain neuronal polarity. The cytoskeletal scaffold ankyrinG is responsible for these functions and clusters ion channels at the AIS. Recent studies reveal how the AIS forms and remarkable diversity in its structure, function, and composition that may be modulated by neuronal activity and posttranslational modifications of AIS proteins...
August 2014: Current Opinion in Neurobiology
Jennifer D Petersen, Stefanie Kaech, Gary Banker
The polarized distribution of membrane proteins to axonal or somatodendritic neuronal compartments is fundamental to nearly every aspect of neuronal function. The polarity of dendritic proteins depends on selective microtubule-based transport; the vesicles that carry these proteins are transported into dendrites but do not enter the axon. We used live-cell imaging of fluorescently tagged dendritic and axonal proteins combined with immunostaining for initial segment and cytoskeletal markers to evaluate different models of dendrite-selective transport in cultured rat hippocampal neurons...
March 19, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Hiroshi Kuba, Ryota Adachi, Harunori Ohmori
The axon initial segment (AIS) is the site of spike initiation in neurons. Previous studies revealed that spatial distribution of the AIS varies greatly among neurons to meet their specific needs. However, when and how this differentiation arises is unknown. Neurons in the avian nucleus laminaris (NL) are binaural coincidence detectors for sound localization and show differentiation in the distribution of the AIS, with shorter length and a more distal position from the soma with an increase in tuning frequency...
February 26, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Wen Dun, John S Lowe, Patrick Wright, Thomas J Hund, Peter J Mohler, Penelope A Boyden
Cardiac Na channel remodeling provides a critical substrate for generation of reentrant arrhythmias in border zones of the infarcted canine heart. Recent studies show that Nav1.5 assembly and function are linked to ankyrin-G, gap, and mechanical junction proteins. In this study our objective is to expound the status of the cardiac Na channel, its interacting protein ankyrinG and the mechanical and gap junction proteins at two different times post infarction when arrhythmias are known to occur; that is, 48 hr and 5 day post coronary occlusion...
2013: PloS One
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