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ACS Chemical Neuroscience Jan 2015A great deal of research has focused on investigating neurobiological alterations induced by chronic psychostimulant use in an effort to describe, understand, and treat... (Review)
Review
A great deal of research has focused on investigating neurobiological alterations induced by chronic psychostimulant use in an effort to describe, understand, and treat the pathology of psychostimulant addiction. It has been known for several decades that dopamine neurotransmission in the nucleus accumbens is integrally involved in the selection and execution of motivated and goal-directed behaviors, and that psychostimulants act on this system to exert many of their effects. As such, a large body of work has focused on defining the consequences of psychostimulant use on dopamine signaling in the striatum as it relates to addictive behaviors. Here, we review presynaptic dopamine terminal alterations observed following self-administration of cocaine and amphetamine, as well as possible mechanisms by which these alterations occur and their impact on the progression of addiction.
Topics: Adaptation, Biological; Animals; Central Nervous System Stimulants; Dopamine; Humans; Presynaptic Terminals; Self Administration
PubMed: 25491345
DOI: 10.1021/cn5002705 -
Neuromolecular Medicine Sep 2015Neurons and especially their synapses often project long thin processes that can invaginate neighboring neuronal or glial cells. These "invaginating projections" can... (Review)
Review
Neurons and especially their synapses often project long thin processes that can invaginate neighboring neuronal or glial cells. These "invaginating projections" can occur in almost any combination of postsynaptic, presynaptic, and glial processes. Invaginating projections provide a precise mechanism for one neuron to communicate or exchange material exclusively at a highly localized site on another neuron, e.g., to regulate synaptic plasticity. The best-known types are postsynaptic projections called "spinules" that invaginate into presynaptic terminals. Spinules seem to be most prevalent at large very active synapses. Here, we present a comprehensive review of all kinds of invaginating projections associated with both neurons in general and more specifically with synapses; we describe them in all animals including simple, basal metazoans. These structures may have evolved into more elaborate structures in some higher animal groups exhibiting greater synaptic plasticity. In addition to classic spinules and filopodial invaginations, we describe a variety of lesser-known structures such as amphid microvilli, spinules in giant mossy terminals and en marron/brush synapses, the highly specialized fish retinal spinules, the trophospongium, capitate projections, and fly gnarls, as well as examples in which the entire presynaptic or postsynaptic process is invaginated. These various invaginating projections have evolved to modify the function of a particular synapse, or to channel an effect to one specific synapse or neuron, without affecting those nearby. We discuss how they function in membrane recycling, nourishment, and cell signaling and explore how they might change in aging and disease.
Topics: Animals; Biological Evolution; Cell Surface Extensions; Humans; Invertebrates; Neuronal Plasticity; Neurons; Paracrine Communication; Post-Synaptic Density; Presynaptic Terminals; Pseudopodia; Species Specificity; Synapses; Vertebrates
PubMed: 26007200
DOI: 10.1007/s12017-015-8358-6 -
Essays in Biochemistry 2015In the CNS (central nervous system), nerve cells communicate by transmitting signals from one to the next across chemical synapses. Electrical signals trigger controlled... (Review)
Review
In the CNS (central nervous system), nerve cells communicate by transmitting signals from one to the next across chemical synapses. Electrical signals trigger controlled secretion of neurotransmitter by exocytosis of SV (synaptic vesicles) at the presynaptic site. Neurotransmitters diffuse across the synaptic cleft, activate receptor channels in the receiving neuron at the postsynaptic site, and thereby elicit a new electrical signal. Repetitive stimulation should result in fast depletion of fusion-competent SVs, given their limited number in the presynaptic bouton. Therefore, to support repeated rounds of release, a fast trafficking cycle is required that couples exocytosis and compensatory endocytosis. During this exo-endocytic cycle, a defined stoichiometry of SV proteins has to be preserved, that is, membrane proteins have to be sorted precisely. However, how this sorting is accomplished on a molecular level is poorly understood. In the present chapter we review recent findings regarding the molecular composition of SVs and the mechanisms that sort SV proteins during compensatory endocytosis. We identify self-assembly of SV components and individual cargo recognition by sorting adaptors as major mechanisms for maintenance of the SV protein complement.
Topics: Adaptor Proteins, Vesicular Transport; Animals; Central Nervous System; Cholesterol; Endocytosis; Exocytosis; Humans; Neurons; Neurotransmitter Agents; Phospholipids; Presynaptic Terminals; Protein Transport; Synaptic Vesicles
PubMed: 25658349
DOI: 10.1042/bse0570121 -
Current Opinion in Neurobiology Apr 2022From a presynaptic perspective, neuronal communication mainly relies on two interdependent events: The fast Ca-triggered fusion of neurotransmitter-containing synaptic... (Review)
Review
From a presynaptic perspective, neuronal communication mainly relies on two interdependent events: The fast Ca-triggered fusion of neurotransmitter-containing synaptic vesicles (SVs) and their subsequent high-fidelity reformation. To allow rapid neurotransmission, SVs have evolved into fascinating molecular nanomachines equipped with a well-defined set of proteins. However, upon exocytosis, SVs fully collapse into the presynaptic plasma membrane leading to the dispersal of their molecular components. While the canonical function of endocytic proteins at the presynapse was believed to be the retrieval of SV proteins via clathrin-mediated endocytosis, it is now evident that clathrin-independent endocytic mechanisms predominate. We will highlight in how far these mechanisms still rely on the classical endocytic machinery and discuss the emerging functions of endocytic proteins in release site clearance and SV reformation from endosomal-like vacuoles.
Topics: Clathrin; Endocytosis; Presynaptic Terminals; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 35217312
DOI: 10.1016/j.conb.2022.01.004 -
The Journal of Neuroscience : the... Apr 2022The presynaptic action potential (AP) is required to drive calcium influx into nerve terminals, resulting in neurotransmitter release. Accordingly, the AP waveform is...
The presynaptic action potential (AP) is required to drive calcium influx into nerve terminals, resulting in neurotransmitter release. Accordingly, the AP waveform is crucial in determining the timing and strength of synaptic transmission. The calyx of Held nerve terminals of rats of either sex showed minimum changes in AP waveform during high-frequency AP firing. We found that the stability of the calyceal AP waveform requires KCNQ (K7) K channel activation during high-frequency spiking activity. High-frequency presynaptic spikes gradually led to accumulation of KCNQ channels in open states which kept interspike membrane potential sufficiently negative to maintain Na channel availability. Blocking KCNQ channels during stimulus trains led to inactivation of presynaptic Na, and to a lesser extent K1 channels, thereby reducing the AP amplitude and broadening AP duration. Moreover, blocking KCNQ channels disrupted the stable calcium influx and glutamate release required for reliable synaptic transmission at high frequency. Thus, while KCNQ channels are generally thought to prevent hyperactivity of neurons, we find that in axon terminals these channels function to facilitate reliable high-frequency synaptic signaling needed for sensory information processing. The presynaptic spike results in calcium influx required for neurotransmitter release. For this reason, the spike waveform is crucial in determining the timing and strength of synaptic transmission. Auditory information is encoded by spikes phase locked to sound frequency at high rates. The calyx of Held nerve terminals in the auditory brainstem show minimum changes in spike waveform during high-frequency spike firing. We found that activation of KCNQ K channel builds up during high-frequency firing and its activation helps to maintain a stable spike waveform and reliable synaptic transmission. While KCNQ channels are generally thought to prevent hyperexcitability of neurons, we find that in axon terminals these channels function to facilitate high-frequency synaptic signaling during auditory information processing.
Topics: Action Potentials; Animals; Calcium; Neurotransmitter Agents; Presynaptic Terminals; Rats; Sodium; Synaptic Transmission
PubMed: 35256530
DOI: 10.1523/JNEUROSCI.0363-20.2022 -
Proceedings of the National Academy of... Apr 2021In nerve cells the genes encoding for αδ subunits of voltage-gated calcium channels have been linked to synaptic functions and neurological disease. Here we show that...
In nerve cells the genes encoding for αδ subunits of voltage-gated calcium channels have been linked to synaptic functions and neurological disease. Here we show that αδ subunits are essential for the formation and organization of glutamatergic synapses. Using a cellular αδ subunit triple-knockout/knockdown model, we demonstrate a failure in presynaptic differentiation evidenced by defective presynaptic calcium channel clustering and calcium influx, smaller presynaptic active zones, and a strongly reduced accumulation of presynaptic vesicle-associated proteins (synapsin and vGLUT). The presynaptic defect is associated with the downscaling of postsynaptic AMPA receptors and the postsynaptic density. The role of αδ isoforms as synaptic organizers is highly redundant, as each individual αδ isoform can rescue presynaptic calcium channel trafficking and expression of synaptic proteins. Moreover, αδ-2 and αδ-3 with mutated metal ion-dependent adhesion sites can fully rescue presynaptic synapsin expression but only partially calcium channel trafficking, suggesting that the regulatory role of αδ subunits is independent from its role as a calcium channel subunit. Our findings influence the current view on excitatory synapse formation. First, our study suggests that postsynaptic differentiation is secondary to presynaptic differentiation. Second, the dependence of presynaptic differentiation on αδ implicates αδ subunits as potential nucleation points for the organization of synapses. Finally, our results suggest that αδ subunits act as transsynaptic organizers of glutamatergic synapses, thereby aligning the synaptic active zone with the postsynaptic density.
Topics: Animals; Calcium Channels; Cells, Cultured; Glutamic Acid; Hippocampus; Mice, Knockout; Presynaptic Terminals; Protein Isoforms; Mice
PubMed: 33782113
DOI: 10.1073/pnas.1920827118 -
Neural Plasticity 2016Shank proteins (Shank1, Shank2, and Shank3) act as scaffolding molecules in the postsynaptic density of many excitatory neurons. Mutations in SHANK genes, in particular... (Review)
Review
Shank proteins (Shank1, Shank2, and Shank3) act as scaffolding molecules in the postsynaptic density of many excitatory neurons. Mutations in SHANK genes, in particular SHANK2 and SHANK3, lead to autism spectrum disorders (ASD) in both human and mouse models. Shank3 proteins are made of several domains-the Shank/ProSAP N-terminal (SPN) domain, ankyrin repeats, SH3 domain, PDZ domain, a proline-rich region, and the sterile alpha motif (SAM) domain. Via various binding partners of these domains, Shank3 is able to bind and interact with a wide range of proteins including modulators of small GTPases such as RICH2, a RhoGAP protein, and PIX, a RhoGEF protein for Rac1 and Cdc42, actin binding proteins and actin modulators. Dysregulation of all isoforms of Shank proteins, but especially Shank3, leads to alterations in spine morphogenesis, shape, and activity of the synapse via altering actin dynamics. Therefore, here, we highlight the role of Shank proteins as modulators of small GTPases and, ultimately, actin dynamics, as found in multiple and models. The failure to mediate this regulatory role might present a shared mechanism in the pathophysiology of autism-associated mutations, which leads to dysregulation of spine morphogenesis and synaptic signaling.
Topics: Actins; Animals; Autistic Disorder; Dendritic Spines; GTP Phosphohydrolases; Humans; Nerve Tissue Proteins; Presynaptic Terminals
PubMed: 27795858
DOI: 10.1155/2016/8051861 -
Reviews in the Neurosciences Jun 2016The main structure in the brain responsible not only for nerve signal transmission but also for its simultaneous regulation is chemical synapse, where presynaptic nerve... (Review)
Review
The main structure in the brain responsible not only for nerve signal transmission but also for its simultaneous regulation is chemical synapse, where presynaptic nerve terminals are of considerable importance providing release of neurotransmitters. Analyzing transport of glutamate, the major excitatory neurotransmitter in the mammalian CNS, the authors suggest that there are two main relatively independent mechanisms at the presynaptic level that can influence the extracellular glutamate concentration, and so signaling, and its regulation. The first one is well-known precisely regulated compound exocytosis of synaptic vesicles containing neurotransmitters stimulated by membrane depolarization, which increases significantly glutamate concentration in the synaptic cleft and initiates glutamate signaling through postsynaptic glutamate receptors. The second one is permanent glutamate turnover across the plasma membrane that occurs without stimulation and is determined by simultaneous non-pathological transporter-mediated release of glutamate thermodynamically synchronized with uptake. Permanent glutamate turnover is responsible for maintenance of dynamic glutamatein/glutamateout gradient resulting in the establishment of a flexible extracellular level of glutamate, which can be unique for each synapse because of dependence on individual presynaptic parameters. These two mechanisms, i.e. exocytosis and transporter-mediated glutamate turnover, are both precisely regulated but do not directly interfere with each other, because they have different intracellular sources of glutamate in nerve terminals for release purposes, i.e. glutamate pool of synaptic vesicles and the cytoplasm, respectively. This duality can set up a presynaptic base for memory consolidation and storage, maintenance of neural circuits, long-term potentiation, and plasticity. Arguments against this suggestion are also considered.
Topics: Amino Acid Transport System X-AG; Animals; Glutamic Acid; Humans; Long-Term Potentiation; Presynaptic Terminals; Synapses; Synaptic Transmission
PubMed: 26812863
DOI: 10.1515/revneuro-2015-0044 -
Movement Disorders : Official Journal... Sep 2022Imaging tools that allow quantification of Parkinson's disease (PD) progression could facilitate the development of disease-modifying therapies. Cross-sectional studies...
BACKGROUND
Imaging tools that allow quantification of Parkinson's disease (PD) progression could facilitate the development of disease-modifying therapies. Cross-sectional studies have shown presynaptic terminal damage in PD patients, but longitudinal data are limited.
OBJECTIVES
The aim of this study was to longitudinally assess loss of presynaptic terminals in general and dopaminergic presynaptic terminals in particular as measures of disease progression in early PD.
METHODS
A total of 27 patients with early PD and 18 age- and sex-matched healthy controls underwent positron emission tomography (PET) with C-UCB-J, a ligand for the brain-wide presynaptic terminal marker SV2A, and with F-FE-PE2I, a highly selective dopamine transporter ligand, in combination with a comprehensive motor and non-motor clinical assessment at baseline (BL) and after 26.5 ± 2.1 months (Y2). SUVR-1 images were calculated and volumes of interest were delineated based on individual 3D T1 magnetic resonance imaging (MRI).
RESULTS
PD patients showed significant 2-year worsening of Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) (off medication) scores, but not of non-motor scores. Motor and non-motor scores in controls did not change significantly over 2 years. F-FE-PE2I binding in caudate and putamen showed significant 2-year decline in the PD group and remained unchanged in controls. Longitudinal decline of striatal F-FE-PE2I binding in PD did not correlate with longitudinal changes in MDS-UPDRS-III scores. C-UCB-J PET did not show any region with significant 2-year change in PD or controls.
CONCLUSIONS
F-FE-PE2I PET showed robust 2-year decline in early PD, but C-UCB-J PET did not. Longitudinal changes in F-FE-PE2I binding did not correlate with clinical motor progression. © 2022 International Parkinson and Movement Disorder Society.
Topics: Cross-Sectional Studies; Humans; Ligands; Parkinson Disease; Positron-Emission Tomography; Presynaptic Terminals
PubMed: 35819412
DOI: 10.1002/mds.29148 -
Neuroscience Research Feb 2018
Topics: Animals; Humans; Neurodegenerative Diseases; Neuronal Plasticity; Presynaptic Terminals; Synapses
PubMed: 29452614
DOI: 10.1016/j.neures.2018.01.004