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Biochimica Et Biophysica Acta Feb 2008Polarized growth of the neuron would logically require some form of membrane traffic to the tip of the growth cone, regulated in conjunction with other trafficking... (Review)
Review
Polarized growth of the neuron would logically require some form of membrane traffic to the tip of the growth cone, regulated in conjunction with other trafficking processes that are common to both neuronal and non-neuronal cells. Unlike axons, dendrites are endowed with membranous organelles of the exocytic pathway extending from the cell soma, including both rough and smooth endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC). Dendrites also have satellite Golgi-like cisternal stacks known as Golgi outposts that have no membranous connections with the somatic Golgi. Golgi outposts presumably serve both general and specific local trafficking needs, and could mediate membrane traffic required for polarized dendritic growth during neuronal differentiation. Recent findings suggest that dendritic growth, but apparently not axonal growth, relies very much on classical exocytic traffic, and is affected by defects in components of both the early and late secretory pathways. Within dendrites, localized processes of recycling endosome-based exocytosis regulate the growth of dendritic spines and postsynaptic compartments. Emerging membrane traffic processes and components that contribute specifically to dendritic growth are discussed.
Topics: Animals; Biological Transport; Dendrites; Exocytosis; Humans; Intracellular Membranes; trans-Golgi Network
PubMed: 18155172
DOI: 10.1016/j.bbamcr.2007.11.011 -
Annual Review of Neuroscience Jul 2013In the olfactory system of Drosophila melanogaster, it is relatively straightforward to target in vivo measurements of neural activity to specific processing channels.... (Review)
Review
In the olfactory system of Drosophila melanogaster, it is relatively straightforward to target in vivo measurements of neural activity to specific processing channels. This, together with the numerical simplicity of the Drosophila olfactory system, has produced rapid gains in our understanding of Drosophila olfaction. This review summarizes the neurophysiology of the first two layers of this system: the peripheral olfactory receptor neurons and their postsynaptic targets in the antennal lobe. We now understand in some detail the cellular and synaptic mechanisms that shape odor representations in these neurons. Together, these mechanisms imply that interesting neural adaptations to environmental statistics have occurred. These mechanisms also place some fundamental constraints on early sensory processing that pose challenges for higher brain regions. These findings suggest some general principles with broad relevance to early sensory processing in other modalities.
Topics: Animals; Drosophila; Odorants; Olfactory Pathways; Olfactory Receptor Neurons; Smell
PubMed: 23841839
DOI: 10.1146/annurev-neuro-062111-150533 -
The EMBO Journal Apr 2006Intracellular membrane trafficking of glutamate receptors at excitatory synapses is critical for synaptic function. However, little is known about the specialized...
Intracellular membrane trafficking of glutamate receptors at excitatory synapses is critical for synaptic function. However, little is known about the specialized trafficking events occurring at the postsynaptic membrane. We have found that two components of the exocyst complex, Sec8 and Exo70, separately control synaptic targeting and insertion of AMPA-type glutamate receptors. Sec8 controls the directional movement of receptors towards synapses through PDZ-dependent interactions. In contrast, Exo70 mediates receptor insertion at the postsynaptic membrane, but it does not participate in receptor targeting. Thus, interference with Exo70 function accumulates AMPA receptors inside the spine, forming a complex physically associated, but not yet fused with the postsynaptic membrane. Electron microscopic analysis of these complexes indicates that Exo70 mediates AMPA receptor insertion directly within the postsynaptic density, rather than at extrasynaptic membranes. Therefore, we propose a molecular and anatomical model that dissects AMPA receptor sorting and synaptic delivery within the spine, and uncovers new functions of the exocyst at the postsynaptic membrane.
Topics: Animals; Carrier Proteins; Cells, Cultured; Dendritic Spines; Hippocampus; Membrane Fusion; Membrane Proteins; Mice; Mutation; Neurons; Organ Culture Techniques; Patch-Clamp Techniques; Protein Transport; Rats; Receptors, AMPA; Synapses; Synaptic Membranes; Synaptic Transmission; Synaptosomes; Vesicular Transport Proteins
PubMed: 16601687
DOI: 10.1038/sj.emboj.7601065 -
Human Molecular Genetics Jun 2017Both transmembrane and extracellular cues, one of which is collagen XIII, regulate the formation and function of the neuromuscular synapse, and their absence results in...
Both transmembrane and extracellular cues, one of which is collagen XIII, regulate the formation and function of the neuromuscular synapse, and their absence results in myasthenia. We show that the phenotypical changes in collagen XIII knock-out mice are milder than symptoms in human patients, but the Col13a1-/- mice recapitulate major muscle findings of congenital myasthenic syndrome type 19 and serve as a disease model. In the lack of collagen XIII neuromuscular synapses do not reach full size, alignment, complexity and function resulting in reduced muscle strength. Collagen XIII is particularly important for the preterminal integrity, and when absent, destabilization of the motor nerves results in muscle regeneration and in atrophy especially in the case of slow muscle fibers. Collagen XIII was found to affect synaptic integrity through binding the ColQ tail of acetylcholine esterase. Although collagen XIII is a muscle-bound transmembrane molecule, it also undergoes ectodomain shedding to become a synaptic basal lamina component. We investigated the two forms' roles by novel Col13a1tm/tm mice in which ectodomain shedding is impaired. While postsynaptic maturation, terminal branching and neurotransmission was exaggerated in the Col13a1tm/tm mice, the transmembrane form's presence sufficed to prevent defects in transsynaptic adhesion, Schwann cell invagination/retraction, vesicle accumulation and acetylcholine receptor clustering and acetylcholinesterase dispersion seen in the Col13a1-/- mice, pointing to the transmembrane form as the major conductor of collagen XIII effects. Altogether, collagen XIII secures postsynaptic, synaptic and presynaptic integrity, and it is required for gaining and maintaining normal size, complexity and functional capacity of the neuromuscular synapse.
Topics: Acetylcholinesterase; Animals; Basement Membrane; Cell Adhesion; Collagen; Collagen Type XIII; Mice; Mice, Knockout; Muscle Proteins; Muscle, Skeletal; Neuromuscular Junction; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic; Synapses; Synaptic Transmission
PubMed: 28369367
DOI: 10.1093/hmg/ddx101 -
Scientific Reports Jan 2016Atomistic molecular dynamics simulations were performed with 13 non-peptidic neurotransmitters (NTs) in three different membrane environments. The results provide...
Atomistic molecular dynamics simulations were performed with 13 non-peptidic neurotransmitters (NTs) in three different membrane environments. The results provide compelling evidence that NTs are divided into membrane-binding and membrane-nonbinding molecules. NTs adhere to the postsynaptic membrane surface whenever the ligand-binding sites of their synaptic receptors are buried in the lipid bilayer. In contrast, NTs that have extracellular ligand-binding sites do not have a similar tendency to adhere to the membrane surface. This finding is a seemingly simple yet important addition to the paradigm of neurotransmission, essentially dividing it into membrane-independent and membrane-dependent mechanisms. Moreover, the simulations also indicate that the lipid composition especially in terms of charged lipids can affect the membrane partitioning of NTs. The revised paradigm, highlighting the importance of cell membrane and specific lipids for neurotransmission, should to be of interest to neuroscientists, drug industry and the general public alike.
Topics: Binding Sites; Cell Membrane; Models, Biological; Models, Molecular; Molecular Conformation; Neurotransmitter Agents; Synapses; Synaptic Membranes; Synaptic Transmission
PubMed: 26782980
DOI: 10.1038/srep19345 -
Lipid Membrane State Change by Catalytic Protonation and the Implications for Synaptic Transmission.Membranes Dec 2021In cholinergic synapses, the neurotransmitter acetylcholine (ACh) is rapidly hydrolyzed by esterases to choline and acetic acid (AH). It is believed that this reaction...
In cholinergic synapses, the neurotransmitter acetylcholine (ACh) is rapidly hydrolyzed by esterases to choline and acetic acid (AH). It is believed that this reaction serves the purpose of deactivating ACh once it has exerted its effect on a receptor protein (AChR). The protons liberated in this reaction, however, may by themselves excite the postsynaptic membrane. Herein, we investigated the response of cell membrane models made from phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidic acid (PA) to ACh in the presence and absence of acetylcholinesterase (AChE). Without a catalyst, there were no significant effects of ACh on the membrane state (lateral pressure change ≤0.5 mN/m). In contrast, strong responses were observed in membranes made from PS and PA when ACh was applied in presence of AChE (>5 mN/m). Control experiments demonstrated that this effect was due to the protonation of lipid headgroups, which is maximal at the pK (for PS: pKCOOH≈5.0; for PA: pKHPO4-≈8.5). These findings are physiologically relevant, because both of these lipids are present in postsynaptic membranes. Furthermore, we discussed evidence which suggests that AChR assembles a lipid-protein interface that is proton-sensitive in the vicinity of pH 7.5. Such a membrane could be excited by hydrolysis of micromolar amounts of ACh. Based on these results, we proposed that cholinergic transmission is due to postsynaptic membrane protonation. Our model will be falsified if cholinergic membranes do not respond to acidification.
PubMed: 35054529
DOI: 10.3390/membranes12010005 -
BMC Neuroscience Feb 2020Synaptic degeneration and accumulation of amyloid β-peptides (Aβ) are hallmarks of the Alzheimer diseased brain. Aβ is synaptotoxic and produced by sequential...
BACKGROUND
Synaptic degeneration and accumulation of amyloid β-peptides (Aβ) are hallmarks of the Alzheimer diseased brain. Aβ is synaptotoxic and produced by sequential cleavage of the amyloid precursor protein (APP) by the β-secretase BACE1 and by γ-secretase. If APP is instead cleaved by the α-secretase ADAM10, Aβ will not be generated. Although BACE1 is considered to be a presynaptic protein and ADAM10 has been reported to mainly localize to the postsynaptic density, we have previously shown that both ADAM10 and BACE1 are highly enriched in synaptic vesicles of rat brain and mouse primary hippocampal neurons.
RESULTS
Here, using brightfield proximity ligation assay, we expanded our previous result in primary neurons and investigated the in situ synaptic localization of ADAM10 and BACE1 in rat and human adult brain using both pre- and postsynaptic markers. We found that ADAM10 and BACE1 were in close proximity with both the presynaptic marker synaptophysin and the postsynaptic marker PSD-95. The substrate APP was also detected both pre- and postsynaptically. Subcellular fractionation confirmed that ADAM10 and BACE1 are enriched to a similar degree in synaptic vesicles and as well as in the postsynaptic density.
CONCLUSIONS
We show that the α-secretase ADAM10 and the β-secretase BACE1 are located in both the pre- and postsynaptic compartments in intact brain sections. These findings increase our understanding of the regulation of APP processing, thereby facilitating development of more specific treatment strategies.
Topics: ADAM10 Protein; Aged; Aged, 80 and over; Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor; Animals; Aspartic Acid Endopeptidases; Brain; Female; Humans; Male; Membrane Proteins; Neurons; Rats, Wistar; Synapses; Synaptophysin
PubMed: 32019490
DOI: 10.1186/s12868-020-0554-0 -
The Journal of Neuroscience : the... Aug 2016In the auditory system, sounds are processed in parallel frequency-tuned circuits, beginning in the cochlea. Auditory nerve fibers reflect this tonotopy and encode...
UNLABELLED
In the auditory system, sounds are processed in parallel frequency-tuned circuits, beginning in the cochlea. Auditory nerve fibers reflect this tonotopy and encode temporal properties of acoustic stimuli by "locking" discharges to a particular stimulus phase. However, physiological constraints on phase-locking depend on stimulus frequency. Interestingly, low characteristic frequency (LCF) neurons in the cochlear nucleus improve phase-locking precision relative to their auditory nerve inputs. This is proposed to arise through synaptic integration, but the postsynaptic membrane's selectivity for varying levels of synaptic convergence is poorly understood. The chick cochlear nucleus, nucleus magnocellularis (NM), exhibits tonotopic distribution of both input and membrane properties. LCF neurons receive many small inputs and have low input thresholds, whereas high characteristic frequency (HCF) neurons receive few, large synapses and require larger currents to spike. NM therefore presents an opportunity to study how small membrane variations interact with a systematic topographic gradient of synaptic inputs. We investigated membrane input selectivity and observed that HCF neurons preferentially select faster input than their LCF counterparts, and that this preference is tolerant of changes to membrane voltage. We then used computational models to probe which properties are crucial to phase-locking. The model predicted that the optimal arrangement of synaptic and membrane properties for phase-locking is specific to stimulus frequency and that the tonotopic distribution of input number and membrane excitability in NM closely tracks a stimulus-defined optimum. These findings were then confirmed physiologically with dynamic-clamp simulations of inputs to NM neurons.
SIGNIFICANCE STATEMENT
One way that neurons represent temporal information is by phase-locking, which is discharging in response to a particular phase of the stimulus waveform. In the auditory system, central neurons are optimized to retain or improve phase-locking precision compared with input from the auditory nerve. However, the difficulty of this computation varies systematically with stimulus frequency. We examined properties that contribute to temporal processing both physiologically and in a computational model. Neurons processing low-frequency input benefit from integration of many weak inputs, whereas those processing higher frequencies progressively lose precision by integration of multiple inputs. Here, we reveal general features of input-output optimization that apply to all neurons that process time varying input.
Topics: Action Potentials; Analysis of Variance; Animals; Animals, Newborn; Auditory Pathways; Chick Embryo; Cochlear Nucleus; Computer Simulation; Electric Stimulation; Excitatory Postsynaptic Potentials; In Vitro Techniques; Models, Neurological; Neurons; Patch-Clamp Techniques; Synaptic Transmission
PubMed: 27511020
DOI: 10.1523/JNEUROSCI.4449-15.2016 -
Molecular Biology of the Cell Nov 2016Neuronal synapses are the fundamental units of neural signal transduction and must maintain exquisite signal fidelity while also accommodating the plasticity that...
Neuronal synapses are the fundamental units of neural signal transduction and must maintain exquisite signal fidelity while also accommodating the plasticity that underlies learning and development. To achieve these goals, the molecular composition and spatial organization of synaptic terminals must be tightly regulated; however, little is known about the regulation of lipid composition and organization in synaptic membranes. Here we quantify the comprehensive lipidome of rat synaptic membranes during postnatal development and observe dramatic developmental lipidomic remodeling during the first 60 postnatal days, including progressive accumulation of cholesterol, plasmalogens, and sphingolipids. Further analysis of membranes associated with isolated postsynaptic densities (PSDs) suggests the PSD-associated postsynaptic plasma membrane (PSD-PM) as one specific location of synaptic remodeling. We analyze the biophysical consequences of developmental remodeling in reconstituted synaptic membranes and observe remarkably stable microdomains, with the stability of domains increasing with developmental age. We rationalize the developmental accumulation of microdomain-forming lipids in synapses by proposing a mechanism by which palmitoylation of the immobilized scaffold protein PSD-95 nucleates domains at the postsynaptic plasma membrane. These results reveal developmental changes in lipid composition and palmitoylation that facilitate the formation of postsynaptic membrane microdomains, which may serve key roles in the function of the neuronal synapse.
Topics: Animals; Cell Membrane; Female; Hippocampus; Lipids; Lipoylation; Male; Membrane Microdomains; Membrane Proteins; Nerve Tissue Proteins; Neurogenesis; Neuronal Plasticity; Post-Synaptic Density; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Synapses; Synaptic Membranes
PubMed: 27535429
DOI: 10.1091/mbc.E16-06-0420 -
Life Science Alliance Jul 2021A purification protocol was developed to identify and analyze the component proteins of a postsynaptic density (PSD) lattice, a core structure of the PSD of excitatory...
A purification protocol was developed to identify and analyze the component proteins of a postsynaptic density (PSD) lattice, a core structure of the PSD of excitatory synapses in the central nervous system. "Enriched"- and "lean"-type PSD lattices were purified by synaptic plasma membrane treatment to identify the protein components by comprehensive shotgun mass spectrometry and group them into minimum essential cytoskeleton (MEC) and non-MEC components. Tubulin was found to be a major component of the MEC, with non-microtubule tubulin widely distributed on the purified PSD lattice. The presence of tubulin in and around PSDs was verified by post-embedding immunogold labeling EM of cerebral cortex. Non-MEC proteins included various typical scaffold/adaptor PSD proteins and other class PSD proteins. Thus, this study provides a new PSD lattice model consisting of non-microtubule tubulin-based backbone and various non-MEC proteins. Our findings suggest that tubulin is a key component constructing the backbone and that the associated components are essential for the versatile functions of the PSD.
Topics: Animals; Cell Membrane; Cerebral Cortex; Cytoskeleton; Female; Hippocampus; Male; Mass Spectrometry; Membrane Proteins; Microtubules; Nerve Tissue Proteins; Post-Synaptic Density; Rats; Rats, Wistar; Synapses; Synaptic Membranes; Tubulin
PubMed: 34006534
DOI: 10.26508/lsa.202000945