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Results: 1 to 10 of 13

Publication Record


Integrin β3 Haploinsufficiency Modulates Serotonin Transport and Antidepressant-Sensitive Behavior in Mice.
Mazalouskas M, Jessen T, Varney S, Sutcliffe JS, Veenstra-VanderWeele J, Cook EH, Carneiro AM
(2015) Neuropsychopharmacology 40: 2015-24
MeSH Terms: Analysis of Variance, Animals, Antidepressive Agents, Biological Transport, Gene Expression Regulation, Humans, Infant, Integrin beta3, Mice, Mice, Transgenic, Neurons, Phosphopyruvate Hydratase, Polymorphism, Genetic, Raphe Nuclei, Serotonin, Serotonin Plasma Membrane Transport Proteins, Serotonin Uptake Inhibitors, Synaptic Membranes
Show Abstract · Added February 15, 2016
Converging lines of evidence have identified genetic interactions between the serotonin transporter (SERT) gene and ITGB3, which encodes the β3 subunit that forms the αIIbβ3 and αvβ3 integrin receptor complexes. Here we examine the consequences of haploinsufficiency in the mouse integrin β3 subunit gene (Itgb3) on SERT function and selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) effectiveness in vivo. Biochemical fractionation studies and immunofluorescent staining of murine brain slices reveal that αvβ3 receptors and SERTs are enriched in presynaptic membranes from several brain regions and that αvβ3 colocalizes with a subpopulation of SERT-containing synapses in raphe nuclei. Notably, we establish that loss of a single allele of Itgb3 in murine neurons is sufficient to decrease 5-HT uptake by SERT in midbrain synaptosomes. Pharmacological assays to elucidate the αvβ3-mediated mechanism of reduced SERT function indicate that decreased integrin β3 subunit expression scales down the population size of active SERT molecules and, as a consequence, lowers the effective dose of SSRIs. These data are consistent with the existence of a subpopulation of SERTs that are tightly modulated by integrin αvβ3 and significantly contribute to global SERT function at 5-HT synapses in the midbrain. Importantly, our screen of a normal human population for single nucleotide polymorphisms in human ITGB3 identified a variant associated with reductions in integrin β3 expression levels that parallel our mouse findings. Thus, polymorphisms in human ITGB3 may contribute to the differential responsiveness of select patients to SSRIs.
0 Communities
1 Members
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18 MeSH Terms
The cell polarity scaffold Lethal Giant Larvae regulates synapse morphology and function.
Staples J, Broadie K
(2013) J Cell Sci 126: 1992-2003
MeSH Terms: Animals, Drosophila Proteins, Drosophila melanogaster, Gene Expression Regulation, Larva, Receptors, Glutamate, Synaptic Membranes, Synaptic Transmission, Tumor Suppressor Proteins
Show Abstract · Added March 29, 2017
Lethal Giant Larvae (LGL) is a cytosolic cell polarity scaffold whose loss dominantly enhances neuromuscular junction (NMJ) synaptic overgrowth caused by loss of the Fragile X Mental Retardation Protein (FMRP). However, direct roles for LGL in NMJ morphological and functional development have not before been tested. Here, we use confocal imaging and two-electrode voltage-clamp electrophysiology at the Drosophila larval NMJ to define the synaptic requirements of LGL. We find that LGL is expressed both pre- and postsynaptically, where the scaffold localizes at the membrane on both sides of the synaptic interface. We show that LGL has a cell autonomous presynaptic role facilitating NMJ terminal branching and synaptic bouton formation. Moreover, loss of both pre- and postsynaptic LGL strongly decreases evoked neurotransmission strength, whereas the frequency and amplitude of spontaneous synaptic vesicle fusion events is increased. Cell-targeted RNAi and rescue reveals separable pre- and postsynaptic LGL roles mediating neurotransmission. We show that presynaptic LGL facilitates the assembly of active zone vesicle fusion sites, and that neuronally targeted rescue of LGL is sufficient to ameliorate increased synaptic vesicle cycling imaged with FM1-43 dye labeling. Postsynaptically, we show that loss of LGL results in a net increase in total glutamate receptor (GluR) expression, associated with the selective elevation of GluRIIB subunit-containing receptors. Taken together, these data indicate that the presynaptic LGL scaffold facilitates the assembly of active zone fusion sites to regulate synaptic vesicle cycling, and that the postsynaptic LGL scaffold modulates glutamate receptor composition and function.
1 Communities
1 Members
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9 MeSH Terms
GPCR mediated regulation of synaptic transmission.
Betke KM, Wells CA, Hamm HE
(2012) Prog Neurobiol 96: 304-21
MeSH Terms: Animals, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Humans, Receptors, G-Protein-Coupled, Synaptic Membranes, Synaptic Transmission
Show Abstract · Added December 10, 2013
Synaptic transmission is a finely regulated mechanism of neuronal communication. The release of neurotransmitter at the synapse is not only the reflection of membrane depolarization events, but rather, is the summation of interactions between ion channels, G protein coupled receptors, second messengers, and the exocytotic machinery itself which exposes the components within a synaptic vesicle to the synaptic cleft. The focus of this review is to explore the role of G protein signaling as it relates to neurotransmission, as well as to discuss the recently determined inhibitory mechanism of Gβγ dimers acting directly on the exocytotic machinery proteins to inhibit neurotransmitter release.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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1 Members
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7 MeSH Terms
Chronic desipramine treatment alters tyrosine hydroxylase but not norepinephrine transporter immunoreactivity in norepinephrine axons in the rat prefrontal cortex.
Erickson SL, Gandhi AR, Asafu-Adjei JK, Sampson AR, Miner L, Blakely RD, Sesack SR
(2011) Int J Neuropsychopharmacol 14: 1219-32
MeSH Terms: Adrenergic Neurons, Adrenergic Uptake Inhibitors, Animals, Antidepressive Agents, Tricyclic, Axons, Cell Membrane, Desipramine, Immunohistochemistry, Infusion Pumps, Implantable, Male, Microscopy, Electron, Transmission, Nerve Tissue Proteins, Norepinephrine Plasma Membrane Transport Proteins, Prefrontal Cortex, Protein Transport, Rats, Rats, Sprague-Dawley, Reproducibility of Results, Synaptic Membranes, Tyrosine 3-Monooxygenase
Show Abstract · Added July 10, 2013
Pharmacological blockade of norepinephrine (NE) reuptake is clinically effective in treating several mental disorders. Drugs that bind to the NE transporter (NET) alter both protein levels and activity of NET and also the catecholamine synthetic enzyme tyrosine hydroxylase (TH). We examined the rat prefrontal cortex (PFC) by electron microscopy to determine whether the density and subcellular distribution of immunolabelling for NET and co-localization of NET with TH within individual NE axons were altered by chronic treatment with the selective NE uptake inhibitor desipramine (DMI). Following DMI treatment (21 d, 15 mg/kg.d), NET-immunoreactive (ir) axons were significantly less likely to co-localize TH. This finding is consistent with reports of reduced TH levels and activity in the locus coeruleus after chronic DMI and indicates a reduction of NE synthetic capacity in the PFC. Measures of NET expression and membrane localization, including the number of NET-ir profiles per tissue area sampled, the number of gold particles per NET-ir profile area, and the proportion of gold particles associated with the plasma membrane, were similar in DMI- and vehicle-treated rats. These findings were verified using two different antibodies directed against distinct epitopes of the NET protein. The results suggest that chronic DMI treatment does not reduce NET expression within individual NE axons in vivo or induce an overall translocation of NET protein away from the plasma membrane in the PFC as measured by ultrastructural immunogold labelling. Our findings encourage consideration of possible post-translational mechanisms for regulating NET activity in antidepressant-induced modulation of NE clearance.
1 Communities
1 Members
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20 MeSH Terms
Dopamine depletion alters phosphorylation of striatal proteins in a model of Parkinsonism.
Brown AM, Deutch AY, Colbran RJ
(2005) Eur J Neurosci 22: 247-56
MeSH Terms: Aging, Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases, Corpus Striatum, Disease Models, Animal, Dopamine, Dopamine and cAMP-Regulated Phosphoprotein 32, Levodopa, Male, Nerve Tissue Proteins, Neural Pathways, Neuronal Plasticity, Parkinsonian Disorders, Phosphoprotein Phosphatases, Phosphoproteins, Phosphorylation, Presynaptic Terminals, Protein Phosphatase 1, Rats, Rats, Sprague-Dawley, Receptors, AMPA, Substantia Nigra, Synaptic Membranes, Up-Regulation
Show Abstract · Added June 21, 2013
Nigrostriatal dopamine depletion disrupts striatal medium spiny neuron morphology in Parkinson's disease and modulates striatal synaptic plasticity in animal models of parkinsonism. We demonstrate that long-term nigrostriatal dopamine depletion in the rat induces evolving changes in the phosphorylation of striatal proteins critical for synaptic plasticity. Dopamine depletion increased the phosphorylation of the alpha isoform of calcium-calmodulin-dependent protein kinase II (CaMKIIalpha) at Thr286, a site associated with enhanced autonomous kinase activity, but did not alter total levels of CaMKIIalpha or other synaptic proteins. Dopamine depletion decreased CaMKIIalpha levels in postsynaptic density-enriched fractions without significant changes in other proteins. The activity of protein phosphatase 1 (PP1), a postsynaptic phosphatase that dephosphorylates CaMKII, is regulated by DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa). Dopamine depletion had no effect on DARPP-32 phosphorylation at Thr34, but increased DARPP-32 phosphorylation at Thr75. Levodopa administration reversed the increased phosphorylation of both CaMKIIalpha and DARPP-32. Normal ageing increased the levels of PP1(gamma1 isoform) but decreased levels of the PP1gamma1-targeting proteins spinophilin and neurabin. Elevated phosphorylations of CaMKIIalpha and DARPP-32 were maintained for up to 20 months after dopamine depletion. However, phosphorylation of the CaMKII-PP1 substrate, Ser831 in the glutamate receptor GluR1 subunit, was increased only after sustained (9-20 months) dopamine depletion. Interaction of ageing-related changes in PP1 with the dopamine depletion-induced changes in CaMKIIalpha may account for enhanced GluR1 phosphorylation only after long-term dopamine depletion. These evolving changes may impact striatal synaptic plasticity, Parkinson's disease progression and the changing efficacy and side-effects associated with dopamine replacement therapy.
0 Communities
3 Members
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25 MeSH Terms
Calcium/calmodulin-dependent protein kinase II and synaptic plasticity.
Colbran RJ, Brown AM
(2004) Curr Opin Neurobiol 14: 318-27
MeSH Terms: Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases, Cell Differentiation, Central Nervous System, Dendrites, Humans, Memory, Neuronal Plasticity, Synapses, Synaptic Membranes, Synaptic Transmission
Show Abstract · Added June 21, 2013
A prominent role for calcium/calmodulin-dependent protein kinase II (CaMKII) in regulation of excitatory synaptic transmission was proposed two decades ago when it was identified as a major postsynaptic density protein. Since then, fascinating mechanisms optimized to fine-tune the magnitude and locations of CaMKII activity have been revealed. The importance of CaMKII activity and autophosphorylation to synaptic plasticity in vitro, and to a variety of learning and memory paradigms in vivo has been demonstrated. Recent progress brings us closer to understanding the regulation of dendritic CaMKII activity, localization, and expression, and its role in modulating synaptic transmission and cell morphology.
0 Communities
2 Members
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12 MeSH Terms
Structural alterations at the neuromuscular junctions of matrix metalloproteinase 3 null mutant mice.
VanSaun M, Herrera AA, Werle MJ
(2003) J Neurocytol 32: 1129-42
MeSH Terms: Agrin, Animals, Cell Differentiation, Excitatory Postsynaptic Potentials, Fluorescent Antibody Technique, Matrix Metalloproteinase 3, Mice, Mice, Knockout, Microscopy, Electron, Neuromuscular Junction, Reaction Time, Receptors, Cholinergic, Synaptic Membranes, Synaptic Transmission, Up-Regulation
Show Abstract · Added May 13, 2014
Matrix metalloproteinases are important regulators of extracellular matrix molecules and cell-cell signaling. Antibodies to matrix metalloproteinase 3 (MMP3) recognize molecules at the frog neuromuscular junction, and MMP3 can remove agrin from synaptic basal lamina (VanSaun & Werle, 2000). To gain insight into the possible roles of MMP3 at the neuromuscular junction, detailed observations were made on the structure and function of the neuromuscular junctions in MMP3 null mutant mice. Striking differences were found in the appearance of the postsynaptic apparatus of MMP3 null mutant mice. Endplates had an increased volume of AChR stained regions within the endplate structure, leaving only small regions devoid of AChRs. Individual postsynaptic gutters were wider, containing prominent lines that represent the AChRs concentrated at the tops of the junctional folds. Electron microscopy revealed a dramatic increase in the number and size of the junctional folds, in addition to ectopically located junctional folds. Electrophysiological recordings revealed no change in quantal content or MEPP frequency, but there was an increase in MEPP rise time in a subset of endplates. No differences were observed in the rate or extent of developmental synapse elimination. In vitro cleavage experiments revealed that MMP3 directly cleaves agrin. Increased agrin immunofluorescence was observed at the neuromuscular junctions of MMP3 null mutant mice. These results provide strong evidence that MMP3 is involved in the control of synaptic structure at the neuromuscular junction and they support the hypothesis that MMP3 is involved in the regulation of agrin at the neuromuscular junction.
0 Communities
1 Members
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15 MeSH Terms
High-resolution localization of clathrin assembly protein AP180 in the presynaptic terminals of mammalian neurons.
Yao PJ, Coleman PD, Calkins DJ
(2002) J Comp Neurol 447: 152-62
MeSH Terms: Adaptor Protein Complex 2, Adaptor Proteins, Vesicular Transport, Animals, Carrier Proteins, Cell Compartmentation, Cerebellum, Clathrin, Exocytosis, Humans, Immunohistochemistry, Macaca fascicularis, Membrane Proteins, Microscopy, Electron, Monomeric Clathrin Assembly Proteins, Presynaptic Terminals, Protein Transport, Rats, Rats, Sprague-Dawley, Retina, Synaptic Membranes, Synaptic Transmission, Synaptic Vesicles
Show Abstract · Added February 12, 2015
Synaptic vesicles (SVs) assemble at the presynaptic compartment through a clathrin-dependent mechanism that involves one or more assembly proteins (APs). The assembly protein AP180 is especially efficient at facilitating clathrin cage formation, but its precise ultrastructural localization in neurons is unknown. Using immunoelectron microscopy, we demonstrate the presynaptic localization of AP180 in axon terminals of rat cerebellar neurons. In contrast, the assembly protein AP2 was associated with both the presynaptic plasma membrane and the cytosolic side of the membrane at postsynaptic and extrasynaptic sites. Furthermore, ultrastructural analysis of primate retina showed that AP180 immunoreactivity was preferentially and highly enriched at ribbon synapses, where glutamate is released tonically at high levels and rapid vesicle turnover is essential. To maintain functional synaptic transmission, neurotransmitter-filled SVs must be readily available, and this requires proper reassembly of new vesicles. The expression of AP180, in addition to AP-2, in the clathrin-mediated endocytic pathway might add another level of control to SV reformation for efficient assembly of clathrin, effectively controlling the size of assembled vesicles and faithfully recovering SV-specific components.
Copyright 2002 Wiley-Liss, Inc.
0 Communities
1 Members
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22 MeSH Terms
Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms.
Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nicoll RA
(2000) Nature 408: 936-43
MeSH Terms: Action Potentials, Animals, COS Cells, Calcium, Calcium Channels, Cerebellum, Disks Large Homolog 4 Protein, Down-Regulation, Excitatory Postsynaptic Potentials, Glutamic Acid, Guanylate Kinases, Hippocampus, Humans, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Mice, Mice, Mutant Strains, Nerve Tissue Proteins, Neurons, Protein Transport, Receptors, AMPA, Synapses, Synaptic Membranes
Show Abstract · Added April 2, 2019
Stargazer, an ataxic and epileptic mutant mouse, lacks functional AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate) receptors on cerebellar granule cells. Stargazin, the mutated protein, interacts with both AMPA receptor subunits and synaptic PDZ proteins, such as PSD-95. The interaction of stargazin with AMPA receptor subunits is essential for delivering functional receptors to the surface membrane of granule cells, whereas its binding with PSD-95 and related PDZ proteins through a carboxy-terminal PDZ-binding domain is required for targeting the AMPA receptor to synapses. Expression of a mutant stargazin lacking the PDZ-binding domain in hippocampal pyramidal cells disrupts synaptic AMPA receptors, indicating that stargazin-like mechanisms for targeting AMPA receptors may be widespread in the central nervous system.
0 Communities
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MeSH Terms
Matrix metalloproteinase-3 removes agrin from synaptic basal lamina.
VanSaun M, Werle MJ
(2000) J Neurobiol 43: 140-9
MeSH Terms: Agrin, Animals, Antibodies, Antibody Specificity, Basement Membrane, Bungarotoxins, Dose-Response Relationship, Drug, Immunohistochemistry, Laminin, Male, Matrix Metalloproteinase 3, Microscopy, Electron, Muscle, Skeletal, Neuromuscular Junction, Rana pipiens, Rhodamines, Synaptic Membranes
Show Abstract · Added May 13, 2014
Agrin, a heparin sulfate proteoglycan, is an integral member of the synaptic basal lamina and plays a critical role in the formation and maintenance of the neuromuscular junction. The N-terminal region of agrin binds tightly to basal lamina, while the C-terminal region interacts with a muscle-specific tyrosine kinase (MuSK) to induce the formation of the postsynaptic apparatus. Although the binding of agrin to basal lamina is tight, the binding of agrin to MuSK has yet to be shown; therefore, basal lamina binding is critical for maintaining the presentation of agrin to MuSK. Here we report evidence that supports our hypothesis that matrix metalloproteinase-3 (MMP-3) is responsible for the removal of agrin from synaptic basal lamina. Antibodies to the hinge region of human MMP-3 recognize molecules concentrated at the frog neuromuscular junction in both cross sections and whole mounts. Electron microscopy of neuromuscular junctions stained with antibodies to MMP-3 reveals that staining is found in the extracellular matrix surrounding the Schwann cell. Treatment of sections from frog anterior tibialis muscle with MMP-3 results in a clear and reproducible removal of agrin immunoreactivity from synaptic basal lamina. The same MMP-3 treatment does not alter anti-laminin staining. These results support our hypothesis that synaptic activity results in the activation of MMP-3 at the neuromuscular junction and that MMP-3 specifically removes agrin from synaptic basal lamina.
Copyright 2000 John Wiley & Sons, Inc.
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17 MeSH Terms