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Current Opinion in Neurobiology Apr 2017Effective adaptation of neural circuit function to a changing environment requires many forms of plasticity. Among these, structural plasticity is one of the most... (Review)
Review
Effective adaptation of neural circuit function to a changing environment requires many forms of plasticity. Among these, structural plasticity is one of the most durable, and is also an intrinsic part of the developmental logic for the formation and refinement of synaptic connectivity. Structural plasticity of presynaptic sites can involve the addition, remodeling, or removal of pre- and post-synaptic elements. However, this requires coordination of morphogenesis and assembly of the subcellular machinery for neurotransmitter release within the presynaptic neuron, as well as coordination of these events with the postsynaptic cell. While much progress has been made in revealing the cell biological mechanisms of postsynaptic structural plasticity, our understanding of presynaptic mechanisms is less complete.
Topics: Animals; Drosophila; Neuronal Plasticity; Presynaptic Terminals; Synaptic Transmission
PubMed: 28388491
DOI: 10.1016/j.conb.2017.03.003 -
Seminars in Cell & Developmental Biology Oct 2019In sympathetic neurons innervating the heart, action potentials activate voltage-gated Ca channels and evoke Ca entry into presynaptic terminals triggering... (Review)
Review
In sympathetic neurons innervating the heart, action potentials activate voltage-gated Ca channels and evoke Ca entry into presynaptic terminals triggering neurotransmitter release. Binding of transmitters to specific receptors stimulates signal transduction pathways that cause changes in cardiac function. The mechanisms contributing to presynaptic Ca dynamics involve regulation of endogenous Ca buffers, in particular the endoplasmic reticulum, mitochondria and cyclic nucleotide targeted pathways. The purpose of this review is to summarize and highlight recent findings about Ca homeostasis in cardiac sympathetic neurons and how modulation of second messengers can drive neurotransmission and affect myocyte excitability in cardiovascular disease. Moreover, we discuss the underlying mechanism of abnormal intracellular Ca homeostasis and signaling in these neurons, and speculate on the role of phosphodiesterases as a therapeutic target to restore normal autonomic transmission in disease states of overactivity.
Topics: Animals; Calcium Channels; Cardiovascular Diseases; Humans; Myocytes, Cardiac; Nucleotides, Cyclic; Phosphoric Diester Hydrolases; Presynaptic Terminals
PubMed: 30658154
DOI: 10.1016/j.semcdb.2019.01.010 -
Nature Neuroscience Apr 2024The formation of mammalian synapses entails the precise alignment of presynaptic release sites with postsynaptic receptors but how nascent cell-cell contacts translate...
The formation of mammalian synapses entails the precise alignment of presynaptic release sites with postsynaptic receptors but how nascent cell-cell contacts translate into assembly of presynaptic specializations remains unclear. Guided by pioneering work in invertebrates, we hypothesized that in mammalian synapses, liprin-α proteins directly link trans-synaptic initial contacts to downstream steps. Here we show that, in human neurons lacking all four liprin-α isoforms, nascent synaptic contacts are formed but recruitment of active zone components and accumulation of synaptic vesicles is blocked, resulting in 'empty' boutons and loss of synaptic transmission. Interactions with presynaptic cell adhesion molecules of either the LAR-RPTP family or neurexins via CASK are required to localize liprin-α to nascent synaptic sites. Liprin-α subsequently recruits presynaptic components via a direct interaction with ELKS proteins. Thus, assembly of human presynaptic terminals is governed by a hierarchical sequence of events in which the recruitment of liprin-α proteins by presynaptic cell adhesion molecules is a critical initial step.
Topics: Animals; Humans; Synapses; Synaptic Transmission; Neurons; Carrier Proteins; Presynaptic Terminals; Cell Adhesion Molecules; Mammals
PubMed: 38472649
DOI: 10.1038/s41593-024-01592-9 -
Free Radical Biology & Medicine Dec 2016Neurodegenerative diseases are a major public health issue worldwide. Some countries, including France, have engaged in research into the causes of Parkinson's disease,... (Review)
Review
Neurodegenerative diseases are a major public health issue worldwide. Some countries, including France, have engaged in research into the causes of Parkinson's disease, Alzheimer's disease, and multiple sclerosis and the management of these patients. It should lead to a better understanding of the mechanisms leading to these diseases including the possible involvement of lipids in their pathogenesis. Parkinson's disease is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein (Lewy bodies). Several in vivo studies have shown a relationship between the lipid profile [cholesterol, oxidized cholesterol products (oxysterols) formed either enzymatically or by auto-oxidation], the use of drugs regulating cholesterol levels, and the development of Parkinson's disease. Several oxysterols are present in the brain and could play a role in the development of this disease, particularly in the accumulation of α-synuclein, and through various side effects, such as oxidation, inflammation, and cell death. Consequently, in Parkinson's disease, some oxysterols could contribute to the pathophysiology of the disease and constitute potential biomarkers or therapeutic targets.
Topics: Cell Death; Cholesterol; Dopaminergic Neurons; Humans; Oxidation-Reduction; Oxysterols; Parkinson Disease; Presynaptic Terminals; Protein Aggregates; Substantia Nigra; alpha-Synuclein
PubMed: 27836779
DOI: 10.1016/j.freeradbiomed.2016.10.008 -
Science China. Life Sciences Sep 2017Noxious stimuli cause pain by activating cutaneous nociceptors. The Aδ- and C-fibers of dorsal root ganglion (DRG) neurons convey the nociceptive signals to the laminae... (Review)
Review
Noxious stimuli cause pain by activating cutaneous nociceptors. The Aδ- and C-fibers of dorsal root ganglion (DRG) neurons convey the nociceptive signals to the laminae I-II of spinal cord. In the dorsal horn of spinal cord, the excitatory afferent synaptic transmission is regulated by the inhibitory neurotransmitter γ-aminobutyric acid and modulators such as opioid peptides released from the spinal interneurons, and by serotonin, norepinepherine and dopamine from the descending inhibitory system. In contrast to the accumulated evidence for these central inhibitors and their neural circuits in the dorsal spinal cord, the knowledge about the endogenous suppressive mechanisms in nociceptive DRG neurons remains very limited. In this review, we summarize our recent findings of the presynaptic suppressive mechanisms in nociceptive neurons, the BNP/NPR-A/PKG/BKCa channel pathway, the FSTL1/α1Na-K ATPase pathway and the activin C/ERK pathway. These endogenous suppressive systems in the mechanoheat nociceptors may also contribute differentially to the mechanisms of nerve injury-induced neuropathic pain or inflammation-induced pain.
Topics: Animals; Ganglia, Spinal; Neural Inhibition; Nociceptors; Pain; Presynaptic Terminals; Synaptic Transmission
PubMed: 28624955
DOI: 10.1007/s11427-017-9061-y -
The Journal of Neuroscience : the... Sep 2020Multiple forms of homeostasis influence synaptic function under diverse activity conditions. Both presynaptic and postsynaptic forms of homeostasis are important, but...
Multiple forms of homeostasis influence synaptic function under diverse activity conditions. Both presynaptic and postsynaptic forms of homeostasis are important, but their relative impact on fidelity is unknown. To address this issue, we studied auditory nerve synapses onto bushy cells in the cochlear nucleus of mice of both sexes. These synapses undergo bidirectional presynaptic and postsynaptic homeostatic changes with increased and decreased acoustic stimulation. We found that both young and mature synapses exhibit similar activity-dependent changes in short-term depression. Experiments using chelators and imaging both indicated that presynaptic Ca influx decreased after noise exposure, and increased after ligating the ear canal. By contrast, Ca cooperativity was unaffected. Experiments using specific antagonists suggest that occlusion leads to changes in the Ca channel subtypes driving neurotransmitter release. Furthermore, dynamic-clamp experiments revealed that spike fidelity primarily depended on changes in presynaptic depression, with some contribution from changes in postsynaptic intrinsic properties. These experiments indicate that presynaptic Ca influx is homeostatically regulated to enhance synaptic fidelity. Homeostatic mechanisms in synapses maintain stable function in the face of different levels of activity. Both juvenile and mature auditory nerve synapses onto bushy cells modify short-term depression in different acoustic environments, which raises the question of what the underlying presynaptic mechanisms are and the relative importance of presynaptic and postsynaptic contributions to the faithful transfer of information. Changes in short-term depression under different acoustic conditions were a result of changes in presynaptic Ca influx. Spike fidelity was affected by both presynaptic and postsynaptic changes after ear occlusion and was only affected by presynaptic changes after noise-rearing. These findings are important for understanding regulation of auditory synapses under normal conditions and also in disorders following noise exposure or conductive hearing loss.
Topics: Animals; Auditory Perception; Calcium; Cochlear Nerve; Cochlear Nucleus; Female; Homeostasis; Male; Mice; Mice, Inbred CBA; Neuronal Plasticity; Noise; Presynaptic Terminals; Synaptic Potentials
PubMed: 32747441
DOI: 10.1523/JNEUROSCI.1175-19.2020 -
Current Opinion in Neurobiology Aug 2017Synaptic plasticity is critical for experience-dependent adjustments of brain function. While most research has focused on the mechanisms that underlie postsynaptic... (Review)
Review
Synaptic plasticity is critical for experience-dependent adjustments of brain function. While most research has focused on the mechanisms that underlie postsynaptic forms of plasticity, comparatively little is known about how neurotransmitter release is altered in a long-term manner. Emerging research suggests that many of the features of canonical 'postsynaptic' plasticity, such as associativity, structural changes and bidirectionality, also characterize long-term presynaptic plasticity. Recent studies demonstrate that presynaptic plasticity is a potent regulator of circuit output and function. Moreover, aberrant presynaptic plasticity is a convergent factor of synaptopathies like schizophrenia, addiction, and Autism Spectrum Disorders, and may be a potential target for treatment.
Topics: Brain; Humans; Mental Disorders; Neuronal Plasticity; Presynaptic Terminals; Synaptic Transmission
PubMed: 28570863
DOI: 10.1016/j.conb.2017.05.011 -
Neuron Feb 2020A major function of GPCRs is to inhibit presynaptic neurotransmitter release, requiring ligand-activated receptors to couple locally to effectors at terminals. The...
A major function of GPCRs is to inhibit presynaptic neurotransmitter release, requiring ligand-activated receptors to couple locally to effectors at terminals. The current understanding of how this is achieved is through receptor immobilization on the terminal surface. Here, we show that opioid peptide receptors, GPCRs that mediate highly sensitive presynaptic inhibition, are instead dynamic in axons. Opioid receptors diffuse rapidly throughout the axon surface and internalize after ligand-induced activation specifically at presynaptic terminals. We delineate a parallel regulated endocytic cycle for GPCRs operating at the presynapse, separately from the synaptic vesicle cycle, which clears activated receptors from the surface of terminals and locally reinserts them to maintain the diffusible surface pool. We propose an alternate strategy for achieving local control of presynaptic effectors that, opposite to using receptor immobilization and enforced proximity, is based on lateral mobility of receptors and leverages the inherent allostery of GPCR-effector coupling.
Topics: Analgesics, Opioid; Animals; Cells, Cultured; Endocytosis; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Presynaptic Terminals; Protein Transport; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Neurotransmitter; Synaptic Vesicles
PubMed: 31837915
DOI: 10.1016/j.neuron.2019.11.016 -
Nature Methods Aug 2014
Topics: Animals; Brain; Presynaptic Terminals; Synaptic Vesicles; Synaptosomes; Vesicular Transport Proteins
PubMed: 25229096
DOI: 10.1038/nmeth.3057 -
Experimental Cell Research Jul 2015Before fusing with the presynaptic plasma membrane to release neurotransmitter into the synaptic cleft synaptic vesicles have to be recruited to and docked at a... (Review)
Review
Before fusing with the presynaptic plasma membrane to release neurotransmitter into the synaptic cleft synaptic vesicles have to be recruited to and docked at a specialized area of the presynaptic nerve terminal, the active zone. Exocytosis of synaptic vesicles is restricted to the presynaptic active zone, which is characterized by a unique and highly interconnected set of proteins. The protein network at the active zone is integrally involved in this process and also mediates changes in release properties, for example in response to alterations in the level of neuronal network activity. In recent years the development of novel techniques has greatly advanced our understanding of the molecular identity of respective active zone components as well as of the ultrastructure of this membranous subcompartment and of the SV release machinery. Furthermore, active zones are now viewed as dynamic structures whose composition and size are correlated with synaptic efficacy. Therefore, the dynamic remodeling of the protein network at the active zone has emerged as one potential mechanism underlying acute and long-term synaptic plasticity. Here, we will discuss this recent progress and its implications for our view of the role of the AZ in synaptic function.
Topics: Adaptor Proteins, Vesicular Transport; Animals; Humans; Neurotransmitter Agents; Presynaptic Terminals; Synaptic Vesicles
PubMed: 25720549
DOI: 10.1016/j.yexcr.2015.02.011