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Vision Research Dec 1993GABA-immunoreactive displaced amacrines were previously shown to make synapses onto neuronal profiles in the ganglion cell layer (GCL) of macaque monkey retina [Koontz,...
GABA-immunoreactive displaced amacrines were previously shown to make synapses onto neuronal profiles in the ganglion cell layer (GCL) of macaque monkey retina [Koontz, Hendrickson and Ryan (1989) Visual Neuroscience, 2, 19-25]. These postsynaptic elements have been investigated further using postembedding immunogold methods for electron microscopy. This paper provides ultrastructural evidence that GABA-immunoreactive profiles are presynaptic to the ganglion cell soma, axon hillock, and axon initial segment in the GCL and its border with the nerve fiber layer (NFL). Some axonal profiles have a dense undercoat and fasciculated microtubules, features that are characteristic of the axon initial segment in many neurons of both central and peripheral nervous systems. These features are confined to small- and medium-diameter (0.2-0.6 microns) axon profiles located near the GCL/NFL border and are not found on axonal profiles lying deep in the NFL, suggesting that the dense-coated region does not extend far along the axon and that the dense-coated region may be narrower than the distal part of the axon. The dense-coated region may correspond to the ganglion cell "narrow segment" recently described in a variety of species using light microscopic methods. The results presented here strengthen our previous hypothesis that GABA-immunoreactive neurons in the GCL provide direct synaptic input to ganglion cells near the site of action potential initiation.
Topics: Aged; Animals; Axons; Humans; Immunohistochemistry; Macaca nemestrina; Male; Microscopy, Electron; Retinal Ganglion Cells; Synapses; gamma-Aminobutyric Acid
PubMed: 8296458
DOI: 10.1016/0042-6989(93)90221-h -
Neuronal Signaling Dec 2021In neurons, the axon and axon initial segment (AIS) are critical structures for action potential initiation and propagation. Their formation and function rely on tight... (Review)
Review
In neurons, the axon and axon initial segment (AIS) are critical structures for action potential initiation and propagation. Their formation and function rely on tight compartmentalisation, a process where specific proteins are trafficked to and retained at distinct subcellular locations. One mechanism which regulates protein trafficking and association with lipid membranes is the modification of protein cysteine residues with the 16-carbon palmitic acid, known as S-acylation or palmitoylation. Palmitoylation, akin to phosphorylation, is reversible, with palmitate cycling being mediated by substrate-specific enzymes. Palmitoylation is well-known to be highly prevalent among neuronal proteins and is well studied in the context of the synapse. Comparatively, how palmitoylation regulates trafficking and clustering of axonal and AIS proteins remains less understood. This review provides an overview of the current understanding of the biochemical regulation of palmitoylation, its involvement in various neurological diseases, and the most up-to-date perspective on axonal palmitoylation. Through a palmitoylation analysis of the AIS proteome, we also report that an overwhelming proportion of AIS proteins are likely palmitoylated. Overall, our review and analysis confirm a central role for palmitoylation in the formation and function of the axon and AIS and provide a resource for further exploration of palmitoylation-dependent protein targeting to and function at the AIS.
PubMed: 34659801
DOI: 10.1042/NS20210005 -
Cell and Tissue Research 1981The axon hillock (AH) and initial segment (IS) of 10 Golgi neurons and 6 basket cells in the cerebellar cortex of the rat were investigated by electron microscopy using...
The axon hillock (AH) and initial segment (IS) of 10 Golgi neurons and 6 basket cells in the cerebellar cortex of the rat were investigated by electron microscopy using serial sections. An average of 10.4 and 11.3 synaptic terminals were observed to establish synaptic contact with the axon hillock region of Golgi and basket cells, respectively. Most of these terminals were identified as the varicosities of the ascending parallel fibers. It is suggested that the focal innervation of AH regions represents an excitatory input pattern which is basically different from the randomly distributed, huge, parallel-fiber input onto the dendritic trees of Golgi and basket cells. In contrast to Golgi and basket neurons, no accumulation of parallel-fiber synapses was observed around the AH of stellate cell. The IS proper of the three neuronal types were devoid of true axo-axonal synapses.
Topics: Animals; Axons; Cerebellar Cortex; Intercellular Junctions; Interneurons; Microscopy, Electron; Rats; Synapses
PubMed: 7249050
DOI: 10.1007/BF00219363 -
Neuroscience Jan 2018The rodent whisker-to-barrel cortex pathway is a classic model to study the effects of sensory experience and deprivation on neuronal circuit formation, not only during... (Review)
Review
The rodent whisker-to-barrel cortex pathway is a classic model to study the effects of sensory experience and deprivation on neuronal circuit formation, not only during development but also in the adult. Decades of research have produced a vast body of evidence highlighting the fundamental role of neuronal activity (spontaneous and/or sensory-evoked) for circuit formation and function. In this context, it has become clear that neuronal adaptation and plasticity is not just a function of the neonatal brain, but persists into adulthood, especially after experience-driven modulation of network status. Mechanisms for structural remodeling of the somatodendritic or axonal domain include microscale alterations of neurites or synapses. At the same time, functional alterations at the nanoscale such as expression or activation changes of channels and receptors contribute to the modulation of intrinsic excitability or input-output relationships. However, it remains elusive how these forms of structural and functional plasticity come together to shape neuronal network formation and function. While specifically somatodendritic plasticity has been studied in great detail, the role of axonal plasticity, (e.g. at presynaptic boutons, branches or axonal microdomains), is rather poorly understood. Therefore, this review will only briefly highlight somatodendritic plasticity and instead focus on axonal plasticity. We discuss (i) the role of spontaneous and sensory-evoked plasticity during critical periods, (ii) the assembly of axonal presynaptic sites, (iii) axonal plasticity in the mature brain under baseline and sensory manipulation conditions, and finally (iv) plasticity of electrogenic axonal microdomains, namely the axon initial segment, during development and in the mature CNS.
Topics: Animals; Axons; Nerve Net; Neuronal Plasticity; Presynaptic Terminals; Rodentia; Somatosensory Cortex
PubMed: 28739523
DOI: 10.1016/j.neuroscience.2017.07.035 -
Cellular and Molecular Life Sciences :... Jul 2021The identification of the membrane periodic skeleton (MPS), composed of a periodic lattice of actin rings interconnected by spectrin tetramers, was enabled by the... (Review)
Review
The identification of the membrane periodic skeleton (MPS), composed of a periodic lattice of actin rings interconnected by spectrin tetramers, was enabled by the development of super-resolution microscopy, and brought a new exciting perspective to our view of neuronal biology. This exquisite cytoskeleton arrangement plays an important role on mechanisms regulating neuronal (dys)function. The MPS was initially thought to provide mainly for axonal mechanical stability. Since its discovery, the importance of the MPS in multiple aspects of neuronal biology has, however, emerged. These comprise its capacity to act as a signaling platform, regulate axon diameter-with important consequences on the efficiency of axonal transport and electrophysiological properties- participate in the assembly and function of the axon initial segment, and control axon microtubule stability. Recently, MPS disassembly has also surfaced as an early player in the course of axon degeneration. Here, we will discuss the current knowledge on the role of the MPS in axonal physiology and disease.
Topics: Animals; Axonal Transport; Axons; Cell Membrane; Cytoskeleton; Humans; Spectrin
PubMed: 34085116
DOI: 10.1007/s00018-021-03867-x -
Journal of Molecular Biology Oct 2021The axon initial segment (AIS) is a distinct neuronal domain, which is responsible for initiating action potentials, and therefore of key importance to neuronal... (Review)
Review
The axon initial segment (AIS) is a distinct neuronal domain, which is responsible for initiating action potentials, and therefore of key importance to neuronal signaling. To determine how it functions, it is necessary to establish which proteins reside there, how they are organized, and what the dynamic features are. Great strides have been made in recent years, and it is now clear that several AIS cytoskeletal and membrane proteins interact to form a higher-order periodic structure. Here we briefly describe AIS function, protein composition and molecular architecture, and discuss perspectives for future structural characterization, and if structure predictions will be able to model complex higher-order assemblies.
Topics: Action Potentials; Animals; Axon Initial Segment; Cytoskeletal Proteins; Humans; Membrane Proteins; Models, Molecular; Neurons; Protein Conformation
PubMed: 34303720
DOI: 10.1016/j.jmb.2021.167176 -
Brain Research Apr 1987An experimentally induced and reversible model of a neuronal storage disease, swainsonine-induced feline alpha-mannosidosis, has been used to study the modifiability of...
An experimentally induced and reversible model of a neuronal storage disease, swainsonine-induced feline alpha-mannosidosis, has been used to study the modifiability of ectopic, axon hillock-associated neurites and their new synaptic contacts. Earlier studies have fully documented that a variety of neuronal storage disorders are characterized by such changes in neuronal geometry and connectivity. Swainsonine administration was ended after 6 months of continuous treatment which had resulted in characteristic signs of alpha-mannosidosis. Studies of this animal 6 months after reversal showed that even though neuronal vacuolation and other CNS changes essentially normalized, ectopic neurites and their synaptic connections were still present and appeared similar to those of another animal which had been treated with swainsonine for the entire 12-month period. These results suggest that once initiated during the disease process, ectopic axon hillock-associated dendrites become an integral part of the soma-dendritic domain of affected neurons and may not be reversible. These findings may have relevance for current attempts to devise therapies involving enzyme replacement for individuals with inherited neuronal storage disease.
Topics: Alkaloids; Animals; Axons; Cats; Cerebral Cortex; Microscopy, Electron; Neurons; Swainsonine; Synapses; alpha-Mannosidosis
PubMed: 3107757
DOI: 10.1016/s0006-8993(87)80025-2 -
Seminars in Cell & Developmental Biology Mar 2014The transmission of information in the brain depends on the highly polarized architecture of neurons. A number of cellular transport processes support this organization,... (Review)
Review
The transmission of information in the brain depends on the highly polarized architecture of neurons. A number of cellular transport processes support this organization, including active targeting of proteins and passive corralling between compartments. The axon initial segment (AIS), which separates the somatodendritic and axonal compartments, has a key role in neuronal physiology, as both the initiation site of action potentials and the gatekeeper of the axonal arborization. Over the years, the AIS main components and their interactions have been progressively unraveled, as well as their role in the AIS assembly and maintenance. Two mechanisms have been shown to contribute to the regulation of protein transport at the AIS: a surface diffusion barrier and an intracellular traffic filter. However, a molecular understanding of these processes is still lacking. In the view of recent results on the AIS cytoskeleton structure, we will discuss how a better knowledge of the AIS architecture can help understanding its role in the regulation of protein transport and the maintenance of axonal identity.
Topics: Animals; Axonal Transport; Axons; Cell Polarity; Cytoskeletal Proteins; Humans; Membrane Proteins; Microtubules; Protein Transport
PubMed: 24239676
DOI: 10.1016/j.semcdb.2013.11.001 -
Proceedings of the National Academy of... Mar 2022SignificanceChandelier cells (ChCs) are a unique type of GABAergic interneuron that form axo-axonic synapses exclusively on the axon initial segment (AIS) of neocortical...
SignificanceChandelier cells (ChCs) are a unique type of GABAergic interneuron that form axo-axonic synapses exclusively on the axon initial segment (AIS) of neocortical pyramidal neurons (PyNs), allowing them to exert powerful yet precise control over PyN firing and population output. The importance of proper ChC function is further underscored by the association of ChC connectivity defects with various neurological conditions. Despite this, the cellular mechanisms governing ChC axo-axonic synapse formation remain poorly understood. Here, we identify microglia as key regulators of ChC axonal morphogenesis and AIS synaptogenesis, and show that disease-induced aberrant microglial activation perturbs proper ChC synaptic development/connectivity in the neocortex. In doing so, such findings highlight the therapeutic potential of manipulating microglia to ensure proper brain wiring.
Topics: Animals; Axon Initial Segment; GABAergic Neurons; Mice; Microglia; Pyramidal Cells; Synapses
PubMed: 35263225
DOI: 10.1073/pnas.2114476119 -
ENeuro 2016In most vertebrate neurons, action potentials are initiated in the axon initial segment (AIS), a specialized region of the axon containing a high density of...
In most vertebrate neurons, action potentials are initiated in the axon initial segment (AIS), a specialized region of the axon containing a high density of voltage-gated sodium and potassium channels. It has recently been proposed that neurons use plasticity of AIS length and/or location to regulate their intrinsic excitability. Here we quantify the impact of neuron morphology on AIS plasticity using computational models of simplified and realistic somatodendritic morphologies. In small neurons (e.g., dentate granule neurons), excitability was highest when the AIS was of intermediate length and located adjacent to the soma. Conversely, neurons having larger dendritic trees (e.g., pyramidal neurons) were most excitable when the AIS was longer and/or located away from the soma. For any given somatodendritic morphology, increasing dendritic membrane capacitance and/or conductance favored a longer and more distally located AIS. Overall, changes to AIS length, with corresponding changes in total sodium conductance, were far more effective in regulating neuron excitability than were changes in AIS location, while dendritic capacitance had a larger impact on AIS performance than did dendritic conductance. The somatodendritic influence on AIS performance reflects modest soma-to-AIS voltage attenuation combined with neuron size-dependent changes in AIS input resistance, effective membrane time constant, and isolation from somatodendritic capacitance. We conclude that the impact of AIS plasticity on neuron excitability will depend largely on somatodendritic morphology, and that, in some neurons, a shorter or more distally located AIS may promote, rather than limit, action potential generation.
Topics: Action Potentials; Animals; Axons; Computer Simulation; Humans; Membrane Potentials; Models, Neurological; Neuronal Plasticity; Neurons
PubMed: 27022619
DOI: 10.1523/ENEURO.0085-15.2016