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Synaptic vesicle

Michael A Rogawski
Since the 1970s, racetams have been in use as cognitive enhancers. Levetiracetam was discovered to have antiseizure activity in animal models and was then found to bind to SV2A in synaptic and endocrine vesicles. Brivaracetam, an analog of levetiracetam, was identified in a medicinal chemistry campaign with the objective of discovering analogs with higher affinity at racetam-binding sites and greater antiseizure potency.
October 20, 2016: Cell
Qian Cai, Prasad Tammineni
Alzheimer's disease (AD) is characterized by brain deposition of amyloid plaques and tau neurofibrillary tangles along with steady cognitive decline. Synaptic damage, an early pathological event, correlates strongly with cognitive deficits and memory loss. Mitochondria are essential organelles for synaptic function. Neurons utilize specialized mechanisms to drive mitochondrial trafficking to synapses in which mitochondria buffer Ca2+ and serve as local energy sources by supplying ATP to sustain neurotransmitter release...
October 20, 2016: Journal of Alzheimer's Disease: JAD
Joan Yw Liu, Cheryl Reeves, Beate Diehl, Antonietta Coppola, Aliya Al-Hajri, Chandrashekar Hoskote, Salim Al Mughairy, Mohamed Tachrount, Michael Groves, Zuzanna Michalak, Kevin Mills, Andrew W McEvoy, Anna Miserocchi, Sanjay M Sisodiya, Maria Thom
OBJECTIVE: This study reports on a novel brain pathology in young patients with Frontal Lobe Epilepsy that is distinct from Focal Cortical Dysplasia. METHODS: Surgical specimens from twenty young adults with frontal lobe epilepsy (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of rapamycin pathway activation and inhibition, cellular autophagy, and synaptic vesicle-mediated trafficking as well as proteomics analysis...
October 20, 2016: Annals of Neurology
Maksim Storozhuk, Elena Kondratskaya, Lyudmila Nikolaenko, Oleg Krishtal
Rapid acidification occurring during synaptic vesicle release can activate acid-sensing ion channels (ASICs) both on pre- and postsynaptic neurons. In the latter case, a fraction of postsynaptic current would be mediated by cation-selective acid-sensing ion channels. Additionally, in both cases, activation of acid-sensing ion channels could modulate synaptic strength by affecting transmitter release and/or sensitivity of postsynaptic receptors. To address potential involvement of acid-sensing ion channels in mediation/modulation of synaptic transmission at hippocampal GABAergic synapses, we studied effects of three structurally different blockers of acid-sensing ion channels on evoked postsynaptic currents using the patch-clamp technique...
October 19, 2016: Molecular Brain
Anna Vavřínová, Michal Behuliak, Josef Zicha
OBJECTIVE: Catecholaminergic system plays an important role in blood pressure regulation and hypertension development. The available information concerning mRNA expression of catecholaminergic system genes in spontaneously hypertensive rats (SHR) are often contradictory. This might be due to various reference genes used as internal controls. We therefore searched for suitable reference genes for gene expression profiling in adrenal medulla and sympathetic ganglia of SHR and Wistar-Kyoto (WKY) rats, which would enable reliable comparison of mRNA expression of genes of catecholaminergic system between these strains...
September 2016: Journal of Hypertension
Pasquale Striano, Vincenzo Belcastro, Antonietta Coppola, Carlo Minetti, Salvatore Striano
INTRODUCTION: Despite optimal medical treatment, up to 30% of patients with epilepsy continue to experience recurrent seizures, and the challenge for new more efficacious and better-tolerated drugs is continuing. New antiepileptic drugs include the evolution of preexisting drugs and new compounds identified through the investigation of additional molecular targets, such as SV2A synaptic vesicle protein, voltage-gated potassium channels, ionotropic and metabotropic glutamate receptors, and gap junctions...
October 5, 2016: Clinical Neuropharmacology
Wolfgang Löscher, Michel Gillard, Zara A Sands, Rafal M Kaminski, Henrik Klitgaard
The synaptic vesicle glycoprotein SV2A belongs to the major facilitator superfamily (MFS) of transporters and is an integral constituent of synaptic vesicle membranes. SV2A has been demonstrated to be involved in vesicle trafficking and exocytosis, processes crucial for neurotransmission. The anti-seizure drug levetiracetam was the first ligand to target SV2A and displays a broad spectrum of anti-seizure activity in various preclinical models. Several lines of preclinical and clinical evidence, including genetics and protein expression changes, support an important role of SV2A in epilepsy pathophysiology...
October 17, 2016: CNS Drugs
Christopher S Medina, Octavian Biris, Tomas L Falzone, Xiaowei Zhang, Amber J Zimmerman, Elaine L Bearer
Microtubule-based motors carry cargo back and forth between the synaptic region and the cell body. Defects in axonal transport result in peripheral neuropathies, some of which are caused by mutations in KIF5A, a gene encoding one of the heavy chain isoforms of conventional kinesin-1. Some mutations in KIF5A also cause severe central nervous system defects in humans. While transport dynamics in the peripheral nervous system have been well characterized experimentally, transport in the central nervous system is less experimentally accessible and until now not well described...
October 14, 2016: NeuroImage
Carrie J Finno, Matthew H Bordbari, Stephanie J Valberg, David Lee, Josi Herron, Kelly Hines, Tamer Monsour, Erica Scott, Danika L Bannasch, James Mickelson, Libin Xu
Specific spontaneous heritable neurodegenerative diseases have been associated with lower serum and cerebrospinal fluid α-tocopherol (α-TOH) concentrations. Equine neuroaxonal dystrophy (eNAD) has similar histologic lesions to human ataxia with vitamin E deficiency caused by mutations in the α-TOH transfer protein gene (TTPA). Mutations in TTPA are not present with eNAD and the molecular basis remains unknown. Given the neuropathologic phenotypic similarity of the conditions, we assessed the molecular basis of eNAD by global transcriptome sequencing of the cervical spinal cord...
October 14, 2016: Free Radical Biology & Medicine
Yan Xu, Christopher C Quinn
Axonal branch formation and synaptogenesis are sequential events that are required for the establishment of neuronal connectivity. However, little is known about how the transition between these two events is regulated. Here, we report that the lin-4 microRNA can regulate the transition between branch formation and synaptogenesis in the PLM axon of C. elegans. The PLM axon grows a collateral branch during the early L1 stage and undergoes synaptogenesis during the late L1 stage. Loss of the lin-4 microRNA disrupts synaptogenesis during the late L1 stage, suggesting that lin-4 promotes synaptogenesis...
October 13, 2016: Developmental Biology
Benjamin E Brummel, Anthony R Braun, Jonathan N Sachs
Using molecular dynamics simulations, we have explored the effect of asymmetric lipids-specifically those that contain one polyunsaturated (PUFA) and one saturated fatty acid chain-on phase separation in heterogeneous membranes. These lipids are prevalent in neuronal membranes, particularly in synaptic membranes, where the Parkinson's Disease protein α-Synuclein (αS) is found. We have therefore explored the relationship between asymmetric, PUFA-containing lipids, and αS. The simulations show that asymmetric lipids partition to the liquid disordered (Ld) phase of canonical raft mixtures because of the highly disordered PUFA chain...
October 12, 2016: Biochimica et Biophysica Acta
Li Ou, Michael J Przybilla, Chester B Whitley
Mucopolysaccharidosis type I (MPS I) is due to deficiency of α-l-iduronidase (IDUA) and subsequent storage of undegraded glycosaminoglycans (GAG). The severe form of the disease, known as Hurler syndrome, is characterized by mental retardation and neurodegeneration of unknown etiology. To identify potential biomarkers and unveil the neuropathology mechanism of MPS I disease, two-dimensional polyacrylamide gel electrophoresis (PAGE) and nanoliquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) were applied to compare proteome profiling of brains from MPS I and control mice (5-month old)...
October 11, 2016: Molecular Genetics and Metabolism
Grace Woodruff, Sol M Reyna, Mariah Dunlap, Rik Van Der Kant, Julia A Callender, Jessica E Young, Elizabeth A Roberts, Lawrence S B Goldstein
We investigated early phenotypes caused by familial Alzheimer's disease (fAD) mutations in isogenic human iPSC-derived neurons. Analysis of neurons carrying fAD PS1 or APP mutations introduced using genome editing technology at the endogenous loci revealed that fAD mutant neurons had previously unreported defects in the recycling state of endocytosis and soma-to-axon transcytosis of APP and lipoproteins. The endocytosis reduction could be rescued through treatment with a β-secretase inhibitor. Our data suggest that accumulation of β-CTFs of APP, but not Aβ, slow vesicle formation from an endocytic recycling compartment marked by the transcytotic GTPase Rab11...
October 11, 2016: Cell Reports
Nicola Strenzke, Rituparna Chakrabarti, Hanan Al-Moyed, Alexandra Müller, Gerhard Hoch, Tina Pangrsic, Gulnara Yamanbaeva, Christof Lenz, Kuan-Ting Pan, Elisabeth Auge, Ruth Geiss-Friedlander, Henning Urlaub, Nils Brose, Carolin Wichmann, Ellen Reisinger
The multi-C2 domain protein otoferlin is required for hearing and mutated in human deafness. Some OTOF mutations cause a mild elevation of auditory thresholds but strong impairment of speech perception. At elevated body temperature, hearing is lost. Mice homozygous for one of these mutations, Otof(I515T/I515T), exhibit a moderate hearing impairment involving enhanced adaptation to continuous or repetitive sound stimulation. In Otof(I515T/I515T) inner hair cells (IHCs), otoferlin levels are diminished by 65%, and synaptic vesicles are enlarged...
October 11, 2016: EMBO Journal
Olusoji A T Afuwape, Catherine R Wasser, Thomas Schikorski, Ege T Kavalali
Earlier studies suggest that spontaneous and evoked neurotransmitter release processes are maintained by synaptic vesicles which are segregated into functionally distinct pools. However, direct interrogation of the link between this putative synaptic vesicle pool heterogeneity and neurotransmission has been difficult. To examine this link, we tagged vesicles with horseradish peroxidase (HRP) - a heme containing plant enzyme - or antibodies against synaptotagmin-1 (syt1). Filling recycling vesicles in hippocampal neurons with HRP and subsequent treatment with hydrogen peroxide (H2 O2 ) modified the properties of neurotransmitter release depending on the route of HRP uptake...
October 10, 2016: Journal of Physiology
John D Murdoch, Christine M Rostosky, Sindhuja Gowrisankaran, Amandeep S Arora, Sandra-Fausia Soukup, Ramon Vidal, Vincenzo Capece, Siona Freytag, Andre Fischer, Patrik Verstreken, Stefan Bonn, Nuno Raimundo, Ira Milosevic
Endophilin-A, a well-characterized endocytic adaptor essential for synaptic vesicle recycling, has recently been linked to neurodegeneration. We report here that endophilin-A deficiency results in impaired movement, age-dependent ataxia, and neurodegeneration in mice. Transcriptional analysis of endophilin-A mutant mice, complemented by proteomics, highlighted ataxia- and protein-homeostasis-related genes and revealed upregulation of the E3-ubiquitin ligase FBXO32/atrogin-1 and its transcription factor FOXO3A...
October 5, 2016: Cell Reports
Sandra-Fausia Soukup, Sabine Kuenen, Roeland Vanhauwaert, Julia Manetsberger, Sergio Hernández-Díaz, Jef Swerts, Nils Schoovaerts, Sven Vilain, Natalia V Gounko, Katlijn Vints, Ann Geens, Bart De Strooper, Patrik Verstreken
Synapses are often far from the soma and independently cope with proteopathic stress induced by intense neuronal activity. However, how presynaptic compartments turn over proteins is poorly understood. We show that the synapse-enriched protein EndophilinA, thus far studied for its role in endocytosis, induces macroautophagy at presynaptic terminals. We find that EndophilinA executes this unexpected function at least partly independent of its role in synaptic vesicle endocytosis. EndophilinA-induced macroautophagy is activated when the kinase LRRK2 phosphorylates the EndophilinA-BAR domain and is blocked in animals where EndophilinA cannot be phosphorylated...
October 5, 2016: Neuron
Annika Öhrfelt, Ann Brinkmalm, Julien Dumurgier, Gunnar Brinkmalm, Oskar Hansson, Henrik Zetterberg, Elodie Bouaziz-Amar, Jacques Hugon, Claire Paquet, Kaj Blennow
BACKGROUND: Synaptic degeneration is a central pathogenic event in Alzheimer's disease that occurs early during the course of disease and correlates with cognitive symptoms. The pre-synaptic vesicle protein synaptotagmin-1 appears to be essential for the maintenance of an intact synaptic transmission and cognitive function. Synaptotagmin-1 in cerebrospinal fluid is a candidate Alzheimer biomarker for synaptic dysfunction that also may correlate with cognitive decline. METHODS: In this study, a novel mass spectrometry-based assay for measurement of cerebrospinal fluid synaptotagmin-1 was developed, and was evaluated in two independent sample sets of patients and controls...
October 3, 2016: Alzheimer's Research & Therapy
Satoshi Sugita, Leland L Fleming, Caleb Wood, Sydney K Vaughan, Matheus P S M Gomes, Wallace Camargo, Ligia A Naves, Vania F Prado, Marco A M Prado, Cristina Guatimosim, Gregorio Valdez
BACKGROUND: Cholinergic dysfunction occurs during aging and in a variety of diseases, including amyotrophic lateral sclerosis (ALS). However, it remains unknown whether changes in cholinergic transmission contributes to age- and disease-related degeneration of the motor system. Here we investigated the effect of moderately increasing levels of synaptic acetylcholine (ACh) on the neuromuscular junction (NMJ), muscle fibers, and motor neurons during development and aging and in a mouse model for amyotrophic lateral sclerosis (ALS)...
2016: Skeletal Muscle
Yan Zhang, Angelo Keramidas, Joseph W Lynch
Zn(2+) is concentrated into presynaptic vesicles at many central synapses and is released into the synaptic cleft by nerve terminal stimulation. There is strong evidence that synaptically released Zn(2+) modulates glutamatergic neurotransmission, although there is debate concerning the peak concentration it reaches in the synaptic cleft. Glycine receptors (GlyRs), which mediate inhibitory neurotransmission in the spinal cord and brainstem, are potentiated by low nanomolar Zn(2+) and inhibited by micromolar Zn(2+)...
2016: Frontiers in Molecular Neuroscience
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