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| Open AccessThe functional organization of excitatory synaptic input to place cells
Hippocampal place cells contribute to navigation and memory formation. Here, the authors use in vivo glutamate imaging to reveal patterns of excitatory input received by place cell dendrites and find more spatially tuned and functionally organized inputs arriving in the place field.
- Michael D. Adoff
- , Jason R. Climer
- & Daniel A. Dombeck
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Article
| Open AccessPKC-phosphorylation of Liprin-α3 triggers phase separation and controls presynaptic active zone structure
Liquid–liquid phase separation may be a mechanism for organizing the presynaptic nerve terminal. Here, the authors show that PKC-mediated phosphorylation of Liprin-α3 triggers phase separation in cell lines and modulates active zone structure and function in primary hippocampal neurons.
- Javier Emperador-Melero
- , Man Yan Wong
- & Pascal S. Kaeser
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Article
| Open AccessCytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects
Mutations in the RNA binding protein FUS are associated with ALS. Here the authors show that in FUS knock-in mice there is a progressive increase in neuronal activity in the frontal cortex which is associated with altered synaptic gene expression.
- Jelena Scekic-Zahirovic
- , Inmaculada Sanjuan-Ruiz
- & Luc Dupuis
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Article
| Open AccessTranssynaptic modulation of presynaptic short-term plasticity in hippocampal mossy fiber synapses
Post‐tetanic potentiation (PTP) is a major form of plasticity at hippocampal mossy fiber synapses and is considered an entirely presynaptic phenomenon. The authors show that mossy fiber PTP not only lacks associativity, but rather shows anti‐associative induction properties, implementing a brake on mossy fiber detonation.
- David Vandael
- , Yuji Okamoto
- & Peter Jonas
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Article
| Open AccessNMDAR-dependent long-term depression is associated with increased short term plasticity through autophagy mediated loss of PSD-95
Long-term depression (LTD) of synaptic strength contributes to circuit remodeling, memory encoding and erasure. Here, the authors show that P2XR- and NMDAR-dependent LTD are associated with distinct and precise molecular modifications that lead to specific modification of synapse function.
- Benjamin Compans
- , Come Camus
- & Eric Hosy
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Article
| Open AccessNeurexins regulate presynaptic GABAB-receptors at central synapses
Neurexins are evolutionarily conserved cell adhesion molecules that tune synapse formation and specification. Here the authors show that neurexins play similar roles in regulating presynaptic GABAB receptors at multiple CNS synapses.
- Fujun Luo
- , Alessandra Sclip
- & Thomas C. Südhof
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Article
| Open AccessMitochondrial hydrogen peroxide positively regulates neuropeptide secretion during diet-induced activation of the oxidative stress response
Mitochondria play a pivotal role in the generation of signals coupling metabolism with neurotransmitter release, though underlying mechanisms remain unknown. Here the authors show that endogenously produced hydrogen peroxide originating from axonal mitochondria functions as a signaling cue to selectively regulate neuropeptide secretion in C. elegans.
- Qi Jia
- & Derek Sieburth
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Article
| Open AccessUnc13A and Unc13B contribute to the decoding of distinct sensory information in Drosophila
The physical distance between synaptic Ca2+ channels and sensors modulates short-term plasticity (STP). Here, the authors show that synaptic release factors Unc13A and Unc13B distinctly couple with Ca2+ channels and contribute to the neural decoding of distinct sensory information in Drosophila.
- Atefeh Pooryasin
- , Marta Maglione
- & Stephan J. Sigrist
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Article
| Open AccessRapid multi-directed cholinergic transmission in the central nervous system
Cholinergic neurons may transmit information via fast synaptic, point-to-point signaling or diffuse, slow extra-synaptic signaling. The authors show that ACh from a single vesicle triggers synchronous miniature currents in two neurons, showing that ACh can spread significant distances to drive rapid ‘synaptic’ signals.
- Santhosh Sethuramanujam
- , Akihiro Matsumoto
- & Gautam B. Awatramani
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Article
| Open AccessThe docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition
α-Synuclein is a presynaptic protein whose aberrant aggregation is associated with Parkinson’s disease. Here, the authors show how αSynuclein-induced docking of synaptic vesicles is modulated by the lipid composition changes typically observed in neurodegeneration using an in vitro system.
- Wing K. Man
- , Bogachan Tahirbegi
- & Giuliana Fusco
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Article
| Open AccessConserved arginine residues in synaptotagmin 1 regulate fusion pore expansion through membrane contact
Synaptotagmin 1 (Syt1) is the calcium sensor for fast synchronous neurotransmitter release but the mechanism by which it functions is still under debate. Here, the authors combine EPR measurements and functional studies and observe that different faces of the Syt1 C2B domain play different roles in regulating neurotransmitter release and they show that the expansion of the fusion pore is mediated by membrane contact of the C2B arginine apex.
- Sarah B. Nyenhuis
- , Nakul Karandikar
- & David S. Cafiso
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Article
| Open AccessAsynchronous release sites align with NMDA receptors in mouse hippocampal synapses
Action potentials induce synchronous and asynchronous release of neurotransmitters. Here, the authors show that the synchronous and asynchronous release sites are aligned with AMPARs and NMDARs, respectively, in mouse hippocampal synapses. This organization allows efficient activation of NMDARs.
- Shuo Li
- , Sumana Raychaudhuri
- & Shigeki Watanabe
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Article
| Open AccessCooperative function of synaptophysin and synapsin in the generation of synaptic vesicle-like clusters in non-neuronal cells
Synaptic vesicle clusters were proposed to represent phase separated condensates. Here, the authors show that only two proteins, synapsin and synaptophysin, are sufficient to make vesicle clusters in fibroblasts which are similar to those found at synapses in morphology and liquid-like properties.
- Daehun Park
- , Yumei Wu
- & Sunghoe Chang
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Article
| Open AccessEthanol abolishes vigilance-dependent astroglia network activation in mice by inhibiting norepinephrine release
The effects of norepinephrine on sensory processing in cortical networks are altered by recreational drugs like ethanol. The authors show that ethanol suppresses the activation of astrocytes by inhibiting norepinephrine release which may contribute to the cognitive effects of alcohol intoxication.
- Liang Ye
- , Murat Orynbayev
- & Martin Paukert
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Article
| Open AccessOpen syntaxin overcomes exocytosis defects of diverse mutants in C. elegans
Opening of the UNC-64/syntaxin closed conformation by UNC-13/Munc13 to form the neuronal SNARE complex is critical for neurotransmitter release. Here the authors show that facilitating the opening of syntaxin enhances exocytosis not only in unc-13 nulls as well as in diverse C. elegans mutants.
- Chi-Wei Tien
- , Bin Yu
- & Shuzo Sugita
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Article
| Open AccessAutism spectrum disorder-like behavior caused by reduced excitatory synaptic transmission in pyramidal neurons of mouse prefrontal cortex
CNTNAP2 or AHI1 are autism-associated genes. Here the authors show using knockdown of the genes that this results in reduced excitatory synaptic transmission in layer 2/3 pyramidal neurons in the prefrontal cortex and is associated with impaired social interaction in mice.
- Hiroaki Sacai
- , Kazuto Sakoori
- & Masanobu Kano
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Article
| Open AccessPolysynaptic inhibition between striatal cholinergic interneurons shapes their network activity patterns in a dopamine-dependent manner
The mechanisms underlying striatal cholinergic interneurons (ChINs) synchronization and its interaction with dopamine release are unclear. Here, the authors showed that polysynaptic inhibition between ChINs shapes their network activity and is mediated by dopaminergic input.
- Matthijs C. Dorst
- , Anna Tokarska
- & Gilad Silberberg
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Article
| Open AccessA petascale automated imaging pipeline for mapping neuronal circuits with high-throughput transmission electron microscopy
Electron microscopy (EM) is the gold standard for biological ultrastructure but acquisition speed is slow, making it unsuitable for large volumes. Here the authors present a parallel imaging pipeline for continuous autonomous imaging with six transmission EMs to image 1 mm3 of mouse cortex in less than 6 months.
- Wenjing Yin
- , Derrick Brittain
- & Nuno Macarico da Costa
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Article
| Open AccessGABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model
GABA transporters expressed in the striatum may affect behaviour. Here the authors investigate the contribution of GABA transporters on astrocytes to the regulation of dopamine release in the striatum, and show decreased expression of GAT-1 and GAT-3 in a mouse model of Parkinsonism.
- Bradley M. Roberts
- , Natalie M. Doig
- & Stephanie J. Cragg
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Article
| Open AccessNeuroligin 2 regulates absence seizures and behavioral arrests through GABAergic transmission within the thalamocortical circuitry
Neuroligins are postsynaptic cell adhesion molecules that are involved in synapse function and autism spectrum disorder. The authors show that NLG2-mediated GABAergic transmission at the thalamic reticular nucleus-thalamic circuit is a common mechanism underlying epileptic seizures and ASD.
- Feng Cao
- , Jackie J. Liu
- & Zhengping Jia
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Article
| Open AccessNMDAR-mediated modulation of gap junction circuit regulates olfactory learning in C. elegans
Neural plasticity underlies learning and is regulated by modulation of gap junctions. Here, the authors show that NMDAR- and CaMKII-mediated cell autonomous downregulation of gap junction molecules in a circuit of interneurons facilitates olfactory learning affecting behavior in C. elegans.
- Myung-Kyu Choi
- , He Liu
- & Yun Zhang
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Article
| Open AccessThe netrin receptor UNC-40/DCC assembles a postsynaptic scaffold and sets the synaptic content of GABAA receptors
The netrin receptor UNC-40/DCC is required to recruit GABAAR at neuromuscular junctions in C. elegans. Here, the authors show that UNC-40/DCC assembles an intracellular synaptic scaffold, regulating the content of GABAAR and inhibitory neurotransmission.
- Xin Zhou
- , Marine Gueydan
- & Jean-Louis Bessereau
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Article
| Open AccessExercise enhances motor skill learning by neurotransmitter switching in the adult midbrain
Exercise promotes motor skill learning via unclear mechanisms. Here, the authors show that running wheel training results in neurotransmitter switching in caudal pedunculopontine nucleus neurons of mice. These neurons project to several brain regions, regulating the acquisition of motor skills.
- Hui-quan Li
- & Nicholas C. Spitzer
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Article
| Open AccessP2X7 receptor inhibition ameliorates dendritic spine pathology and social behavioral deficits in Rett syndrome mice
P2X7 receptors are purinergic receptors with pro-inflammatory functions. Here, the authors show that inhibition of leukocyte P2X7 receptors reduces dendritic spine pathology and social behavioral deficits in a mouse model of Rett syndrome.
- Juan Mauricio Garré
- , Hernandez Moura Silva
- & Guang Yang
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Article
| Open AccessAutomated highly multiplexed super-resolution imaging of protein nano-architecture in cells and tissues
Super-resolution imaging of multiple target proteins in the same sample can provide important information of cellular nanostructure, but has not been routinely achieved. Here, the authors present a fully automated 3D STORM approach using a re-staining protocol to image 15 targets in single cells and 16 targets in neuronal tissue.
- Maja Klevanski
- , Frank Herrmannsdoerfer
- & Thomas Kuner
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Article
| Open AccessSynaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats
Synaptic dysfunction is hypothesised to play a key role in schizophrenia pathogenesis. Here, using [11C]UCB-J PET, the authors show for the first time in vivo that levels of the synaptic marker protein SV2A are reduced in schizophrenia and unaffected by antipsychotic treatment in a rat model.
- Ellis Chika Onwordi
- , Els F. Halff
- & Oliver D. Howes
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Article
| Open AccessResolving kinetic intermediates during the regulated assembly and disassembly of fusion pores
SNAREs mediate the formation of a fusion pore during exocytosis which connects the lumen of a vesicle with the extracellular space. Here, authors use single molecule approaches to define the role of synaptotagmin 1 and NSF in synaptic pore formation and dissolution.
- Debasis Das
- , Huan Bao
- & Edwin R. Chapman
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Article
| Open AccessSIPA1L2 controls trafficking and local signaling of TrkB-containing amphisomes at presynaptic terminals
There is growing evidence that autophagy might serve specialized functions in neurons besides its role in protein homeostasis. In this study, authors demonstrate that axonal retrograde transport of BDNF/TrkB in neuronal amphisomes is involved in plasticity-relevant local signaling at presynaptic boutons and that SIPA1L2, a member of the SIPA1L family of neuronal RapGAPs, associates via LC3b to TrkB-containing amphisomes to regulate its motility and signaling at the axon terminals
- Maria Andres-Alonso
- , Mohamed Raafet Ammar
- & Michael R. Kreutz
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Article
| Open AccessTsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility
Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 genes, which negatively regulate mTORC1 signalling. Here the authors selectively delete Tsc1 from dopamine neurons in mice and find impairments in striatal dopamine release that are sufficient to reduce cognitive flexibility.
- Polina Kosillo
- , Natalie M. Doig
- & Helen S. Bateup
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Article
| Open AccessPrefrontal cortical ChAT-VIP interneurons provide local excitation by cholinergic synaptic transmission and control attention
VIP interneurons have been shown to disinhibit pyramidal neurons by inhibiting other interneuron types. Here, the authors report that ChAT-VIP subtype of interneurons directly excite pyramidal neurons in multiple layers via fast cholinergic neurotransmission.
- Joshua Obermayer
- , Antonio Luchicchi
- & Huibert D. Mansvelder
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Article
| Open AccessAMPA receptors in the synapse turnover by monomer diffusion
The mechanisms regulating the turnover of the AMPARs in the synapse, which is critically important to sustain basic synaptic activity, remains unclear. In this study, authors used single-molecule imaging techniques to demonstrate that AMPAR tetramers are not stable entities and readily fall apart to dimers and monomers that could reform to tetramers at the synapse, and that rapidly diffusing monomers in the plasma membrane are primarily responsible for the AMPAR turnover in the synapse.
- Jyoji Morise
- , Kenichi G. N. Suzuki
- & Shogo Oka
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Article
| Open AccessThe landscape of multiscale transcriptomic networks and key regulators in Parkinson’s disease
Parkinson’s disease (PD) is characterized by neurodegeneration associated with loss of dopaminergic (DA) neurons and deposition of Lewy bodies. Here, Wang et al. use co-expression network analysis to pinpoint disease pathways and propose reduced expression of STMN2 as a cause of presynaptic function loss in PD.
- Qian Wang
- , Yuanxi Zhang
- & Bin Zhang
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Article
| Open AccessReduced mu opioid receptor availability in schizophrenia revealed with [11C]-carfentanil positron emission tomographic Imaging
Post-mortem studies have suggested a possible reduction in mu-opioid receptor (MOR) density in people with schizophrenia. Here, the authors examined MOR in living patients with schizophrenia using PET imaging, and found local reductions of MOR compared to controls.
- Abhishekh H. Ashok
- , Jim Myers
- & Oliver D. Howes
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Article
| Open AccessMunc18-1 is crucial to overcome the inhibition of synaptic vesicle fusion by αSNAP
Munc18-1 and Munc13-1 are key for the exquisite regulation of neurotransmitter release. Here biophysical experiments show how αSNAP inhibits liposome fusion mediated by the neuronal SNAREs and how Munc18-1 overcomes this inhibition, ensuring that release depends on Munc18-1 and Munc13-1.
- Karolina P. Stepien
- , Eric A. Prinslow
- & Josep Rizo
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| Open AccessSynaptotagmin 1 clamps synaptic vesicle fusion in mammalian neurons independent of complexin
The molecular identity of the clamp that arrests the fusion machinery such that synaptic vesicles are docked and primed to release neurotransmitters remains controversial. In this study, the authors use truncation mutants of synaptotagmin (syt) 1 and animal models to demonstrate that the C2B domain of syt1, and not complexin, is solely responsible for the reduction of the spontaneous release at the presynapse
- Nicholas A. Courtney
- , Huan Bao
- & Edwin R. Chapman
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Article
| Open AccessSynaptotagmin 17 controls neurite outgrowth and synaptic physiology via distinct cellular pathways
The functional role of synaptotagmin-17 (syt-17) has remained unanswered. In this study, authors demonstrate that syt-17 exists in two distinct pools in hippocampal neurons (Golgi complex and early endosomes), where it served two completely independent functions: controlling neurite outgrowth and synaptic physiology
- David A. Ruhl
- , Ewa Bomba-Warczak
- & Edwin R. Chapman
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Article
| Open AccessAsymmetric ephaptic inhibition between compartmentalized olfactory receptor neurons
In Drosophila antenna, an unusual non-synaptic form of lateral inhibition occurs between subtypes of compartmentalized olfactory receptor neurons (ORNs). Here, authors show that direct electrical (ephaptic) interactions mediate lateral inhibition between ORNs, with physically larger ORNs dominating ephaptic interactions.
- Ye Zhang
- , Tin Ki Tsang
- & Chih-Ying Su
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Article
| Open AccessMultiplex imaging relates quantal glutamate release to presynaptic Ca2+ homeostasis at multiple synapses in situ
How neurotransmitter release relates to presynaptic calcium dynamics is not fully understood. Here the authors develop an approach based on FLIM and optical quantal analysis for simultaneous imaging of calcium dynamics and glutamate release at presynaptic boutons.
- Thomas P. Jensen
- , Kaiyu Zheng
- & Dmitri A. Rusakov
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Article
| Open AccessUnderpinning heterogeneity in synaptic transmission by presynaptic ensembles of distinct morphological modules
The mechanisms underlying synaptic heterogeneity of neurotransmission at mature calyx synapses remain unclear. Here, authors identify two morphological modules that have distinct topology of calcium channel clusters and spatial coupling distance to synaptic vesicles, which may account for different release probability and short-term plasticity in calyces with differing morphology.
- Adam Fekete
- , Yukihiro Nakamura
- & Lu-Yang Wang
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Article
| Open AccessTime-dependent assessment of stimulus-evoked regional dopamine release
It has proven difficult to measure the release of neurotransmitters, such as dopamine, in the human brain. Here, the authors introduce and validate a new method that infers dopamine release based on minute-by-minute fluctuations of the positron emission tomography (PET) radioligand [11C]raclopride.
- Rachel N. Lippert
- , Anna Lena Cremer
- & Heiko Backes
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Article
| Open AccessMunc18 and Munc13 serve as a functional template to orchestrate neuronal SNARE complex assembly
Synaptic exocytosis depends on formation of the SNARE complex but its assembly mechanism is still under debate. Here, the authors identify an interaction between Munc13-1 and synaptobrevin-2 that is critical for the transition of the Munc18-1/syntaxin-1 complex to the SNARE complex.
- Shen Wang
- , Yun Li
- & Cong Ma
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Article
| Open AccessIgSF9b regulates anxiety behaviors through effects on centromedial amygdala inhibitory synapses
IgSF9b is a synaptic adhesion protein that has been linked to psychiatric disorders. Here the authors show that deletion of IgSF9b regulates anxiety-like behaviour in mice by increasing inhibitory synaptic transmission in the centromedial amygdala.
- Olga Babaev
- , Hugo Cruces-Solis
- & Dilja Krueger-Burg
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Article
| Open AccessSignal peptide represses GluK1 surface and synaptic trafficking through binding to amino-terminal domain
The two kainate receptors GluK1 and GluK2 show different surface expression and synaptic trafficking. Here authors engineer chimeric GluK1-GluK2 receptors and decipher a role how the signal peptide of GluK1 behaves as a ligand of GluK1 and modifies surface expression and trafficking.
- Gui-Fang Duan
- , Yaxin Ye
- & Nengyin Sheng
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Article
| Open AccessUnmasking GluN1/GluN3A excitatory glycine NMDA receptors
Excitatory glycine GluN1/GluN3A receptors are atypical NMDARs that have been difficult to study. Here the authors identify new properties of these receptors, including potentiation by the GluN1 antagonist CGP-78608 that allows detection of functional GluN1/GluN3A receptors in the juvenile brain.
- Teddy Grand
- , Sarah Abi Gerges
- & Pierre Paoletti
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Article
| Open AccessSystemic neurotransmitter responses to clinically approved and experimental neuropsychiatric drugs
The precise relationship between neurobehavioural effects and neurotransmitter effects of psychiatric drugs are not always understood. Here the authors develop a database documenting the neurotransmitter response in rats to 258 different neuropsychiatric drugs, and conclude that this neurotransmitter response does not, in general, reflect the current categorisation of those drugs.
- Hamid R. Noori
- , Lewis H. Mervin
- & Rainer Spanagel
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Article
| Open AccessAstrocytes detect and upregulate transmission at inhibitory synapses of somatostatin interneurons onto pyramidal cells
Astrocytes have been shown to regulate glutamatergic transmission in the brain. Here, the authors show that astrocytes also detect and modulate GABAergic transmission from somatostatin but not parvalbumin-positive interneurons, thus regulating dendritic inhibition via a feedback loop.
- Marco Matos
- , Anthony Bosson
- & Jean-Claude Lacaille
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Article
| Open AccessFocused clamping of a single neuronal SNARE complex by complexin under high mechanical tension
The SNARE complex enables the fusion of synaptic vesicles with presynaptic membrane via a zippering process that is modulated by the protein complexin, though the precise mechanism remains unclear. Here, the authors used magnetic tweezers to show how complexin prepares a SNARE complex for fusion under mechanical tension.
- Min Ju Shon
- , Haesoo Kim
- & Tae-Young Yoon
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Correspondence
| Open AccessReply to ‘Antipsychotics with similar association kinetics at dopamine D2 receptors differ in extrapyramidal side-effects’
- David A. Sykes
- , J. Robert Lane
- & Steven J. Charlton
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Correspondence
| Open AccessAntipsychotics with similar association kinetics at dopamine D2 receptors differ in extrapyramidal side-effects
- Hugo Zeberg
- & Kristoffer Sahlholm