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| Open AccessSpecification of neural circuit architecture shaped by context-dependent patterned LAR-RPTP microexons
LAR-RPTPs are presynaptic cell-adhesion proteins that regulate the synaptic properties. Here, LAR-RPTP microexon expression is profiled in region-, cell-type- and circuit-specific contexts and its physiological significance in encoding synaptic architecture is demonstrated.
- Kyung Ah Han
- , Taek-Han Yoon
- & Jaewon Ko
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Article
| Open AccessA presynaptic source drives differing levels of surround suppression in two mouse retinal ganglion cell types
Compartments of neurons can sometimes act as independent computational units. Here the authors show that retinal bipolar cells, some of the smallest mammalian neurons, send different signals to downstream ganglion cells via different synapses.
- David Swygart
- , Wan-Qing Yu
- & Gregory W. Schwartz
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Article
| Open AccessComplex 33-beam simulated galactic cosmic radiation exposure impacts cognitive function and prefrontal cortex neurotransmitter networks in male mice
Here the authors show in male mice that acute and chronic complex simulated galactic cosmic radiation exposure differentially reorganized prefrontal cortex neurotransmitter networks in vivo, which was associated with cognitive deficits.
- Rajeev I. Desai
- , Brian D. Kangas
- & Charles L. Limoli
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Article
| Open AccessPatient-specific models link neurotransmitter receptor mechanisms with motor and visuospatial axes of Parkinson’s disease
Neurotransmitter receptor distributions help explain structural and functional brain alterations in Parkinson’s disease. Distinct multi-receptor profiles are associated with the severity of motor, and visuospatial, psychiatric and memory symptoms.
- Ahmed Faraz Khan
- , Quadri Adewale
- & Yasser Iturria-Medina
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Article
| Open AccessNeurexin-3 subsynaptic densities are spatially distinct from Neurexin-1 and essential for excitatory synapse nanoscale organization in the hippocampus
How do individual neurexins control distinct synaptic properties? Here, the authors show that the nanoscopic properties of Nrxn1 and Nrxn3 are spatially discrete and propose a model where Nrxn1 and Nrxn3 signal in parallel to control synapse function.
- Brian A Lloyd
- , Ying Han
- & Jason Aoto
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Article
| Open AccessMechanisms of simultaneous linear and nonlinear computations at the mammalian cone photoreceptor synapse
Cone photoreceptors signal to several bipolar cell types at one of the most structurally complex synapses in the central nervous system. Here, the authors show how the 3D organization of this synapse creates different signals in the postsynaptic OFF bipolar cell types.
- Chad P. Grabner
- , Daiki Futagi
- & Steven H. DeVries
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Article
| Open AccessAfferent convergence to a shared population of interneuron AMPA receptors
Glutamate that diffuses out of the synaptic cleft can have actions at distant receptors, a mode of transmission called spillover. Here, the authors find in the cerebellar cortex that glutamate spillover from climbing fibers activates synaptic AMPA receptors of molecular layer interneurons, allowing glutamate from an unconnected pathway to co-opt postsynaptic receptors.
- Reagan L. Pennock
- , Luke T. Coddington
- & Jacques I. Wadiche
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Article
| Open AccessVesicular glutamate transporters are H+-anion exchangers that operate at variable stoichiometry
In glutamatergic neurons, synaptic vesicles contain glutamate, but not aspartate. Here, the authors show that vesicular glutamate transporters are H+/anion exchangers that attain high selectivity for glutamate via variable transport coupling.
- Bettina Kolen
- , Bart Borghans
- & Christoph Fahlke
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Article
| Open AccessControl of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43
Cannabis impacts our brain by engaging the CB1 receptor. Here, the authors identify a protein called GAP43 that interacts with CB1 and blocks its synaptic functions. This finding provides a conceptual view to understand how CB1 acts in the brain.
- Irene B. Maroto
- , Carlos Costas-Insua
- & Manuel Guzmán
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Article
| Open AccessDeterminants of functional synaptic connectivity among amygdala-projecting prefrontal cortical neurons in male mice
Little is known about the synaptic organization of associative cortical structures such as the medial prefrontal cortex. Here, the authors use two-photon optogenetic stimulation to obtain a detailed cellular resolution map of functional synaptic connectivity of the mouse medial prefrontal cortex, finding unique spatial patterns of local-circuit connectivity in neurons that project to the basolateral amygdala.
- Yoav Printz
- , Pritish Patil
- & Ofer Yizhar
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Article
| Open AccessTwo gates mediate NMDA receptor activity and are under subunit-specific regulation
NMDA receptors are glutamate-gated ion channels that regulate fast signaling in the brain. Here, the authors show that the opening and closing patterns of the channel derive from the action of two gates that are regulated by distinct subunits.
- Johansen B. Amin
- , Miaomiao He
- & Lonnie P. Wollmuth
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Article
| Open AccessVesicular release probability sets the strength of individual Schaffer collateral synapses
It is not fully understood if the probability of synaptic vesicle release is homogenous or varies between individual boutons. Here the authors perform optical quantal analyses of individual Schaffer collateral synapses, showing that multivesicular release enables a tenfold increase in glutamate output and that the vesicular release probability is not uniform between synapses.
- Céline D. Dürst
- , J. Simon Wiegert
- & Thomas G. Oertner
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Article
| Open AccessSLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice
The protein SLITRK2 plays an important role in synaptic communication. This study identifies X-linked SLITRK2 variants that underlie neurodevelopmental disorders by impairing excitatory synapses.
- Salima El Chehadeh
- , Kyung Ah Han
- & Ji Won Um
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Article
| Open AccessA synaptomic analysis reveals dopamine hub synapses in the mouse striatum
The neurotransmitter dopamine is an important regulator of brain function. Here the authors describe “dopamine hub synapses”, where dopamine transmission may act in synergy with other neurotransmitters.
- Vincent Paget-Blanc
- , Marlene E. Pfeffer
- & Etienne Herzog
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Article
| Open AccessNanoscale rules governing the organization of glutamate receptors in spine synapses are subunit specific
Glutamate receptors comprise two obligate subunits and two subunits that confer distinct properties and functions to the specific tetramers, which also localize to distinct synaptic spines. Here, the authors use STimulated Emission Depletion nanoscopy (STED) to provide detailed insights into the spatial organization of glutamate receptor types.
- Martin Hruska
- , Rachel E. Cain
- & Matthew B. Dalva
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Article
| Open AccessSchizophrenia-associated SAP97 mutations increase glutamatergic synapse strength in the dentate gyrus and impair contextual episodic memory in rats
The effects of SAP97 mutations associated with schizophrenia on synaptic function are unclear. Here, the authors show that schizophrenia-related SAP97 mutations enhance glutamatergic synapse strength in the dentate gyrus, impairing contextual episodic memory in rats.
- Yuni Kay
- , Linda Tsan
- & Bruce E. Herring
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Article
| Open AccessPhysiological synaptic activity and recognition memory require astroglial glutamine
The authors present a fluorescent probe that tracks glutamine in live cells. They demonstrate the capabilities of the probe by providing direct visual evidence of an activity-dependent glutamine supply from astroglial networks to presynaptic structures under physiological conditions.
- Giselle Cheung
- , Danijela Bataveljic
- & Nathalie Rouach
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Article
| Open AccessExcitatory synapses and gap junctions cooperate to improve Pv neuronal burst firing and cortical social cognition in Shank2-mutant mice
How NMDAR and GABA neuronal dysfunctions result in impaired social behaviour is unclear. Here, the authors show that NMDARs and gap junctions in cortical PV interneurons modulate burst firing, affecting social behaviour.
- Eunee Lee
- , Seungjoon Lee
- & Eunjoon Kim
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Article
| Open AccessAMPA receptor anchoring at CA1 synapses is determined by N-terminal domain and TARP γ8 interactions
Changes in AMPAR localization can control the strength of synaptic transmission. Here, the authors show that the interactions of TARP γ8 and the AMPAR N-terminal domain work together to regulate receptor accumulation and positioning at the post-synapse of mouse hippocampal CA1 neurons.
- Jake F. Watson
- , Alexandra Pinggera
- & Ingo H. Greger
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Article
| 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 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 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 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 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 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 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 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 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 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 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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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
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Article
| Open AccessThe sulfite oxidase Shopper controls neuronal activity by regulating glutamate homeostasis in Drosophila ensheathing glia
In Drosophila, ensheathing glia encase the neuropil but their function is not well understood. Here the authors show a surprising role of ensheathing glia in regulating glutamate homeostasis and locomotion which is controlled by the sulfite oxidase Shopper.
- Nils Otto
- , Zvonimir Marelja
- & Christian Klämbt
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Article
| Open AccessVti1a/b regulate synaptic vesicle and dense core vesicle secretion via protein sorting at the Golgi
Vti1a and Vti1b are SNARE proteins implicated in regulated secretion. Here the authors show that Vti1a and Vti1b control protein sorting at the Golgi, and targeting to the axon, and thereby indirectly control regulated secretion at the synapse.
- Javier Emperador-Melero
- , Vincent Huson
- & Matthijs Verhage
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Article
| Open AccessDevelopmental seizures and mortality result from reducing GABAA receptor α2-subunit interaction with collybistin
The inhibitory synaptic protein collybistin (CB) and GABAAR-α subunits are thought to interact, but strength and specificity are unclear. Here the authors study the CB–α2 interaction and show that a mouse mutated in the CB-binding region of α2 displays a loss of specific synapses and seizure.
- Rochelle M. Hines
- , Hans Michael Maric
- & Stephen J. Moss
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Article
| Open AccessCo-transmission of acetylcholine and GABA regulates hippocampal states
Acetylcholine (ACh) release in the central nervous system is thought to be unitary and mediated non-synaptically in volume transmission. Here, Takács and colleagues show cholinergic terminals juxtapose GABAergic synapses anatomically and functionally, and GABA and ACh molecules are co-transmitted.
- Virág T. Takács
- , Csaba Cserép
- & Gábor Nyiri
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Article
| Open AccessAlcohol exposure disrupts mu opioid receptor-mediated long-term depression at insular cortex inputs to dorsolateral striatum
µ-opioid receptors (MOR) are known to modulate the reward effects of drugs of abuse, and MOR activation induces long-term depression (LTD) at striatal synapses. Here the authors show that alcohol exposure disrupts MOR-induced LTD only at specific cortical inputs to the striatum.
- Braulio Muñoz
- , Brandon M. Fritz
- & Brady K. Atwood
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Article
| Open AccessVGLUT1 functions as a glutamate/proton exchanger with chloride channel activity in hippocampal glutamatergic synapses
During neurotransmission synaptic vesicles are filled with glutamate by vesicular glutamate transporters (VGLUTs). Here, authors image intact neurons and show that in synaptic vesicles VGLUT functions as a glutamate/proton exchanger associated with a channel-like chloride conductance.
- Magalie Martineau
- , Raul E. Guzman
- & Jürgen Klingauf
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Article
| Open AccessGABAA receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl−-sensitive WNK1 kinase
GABAergic transmission regulates the K+-Cl− co-transporter KCC2. Here the authors demonstrate that inhibitory transmission, via GABAA receptor and WNK signaling, regulates KCC2 expression in the membrane of hippocampal neurons.
- Martin Heubl
- , Jinwei Zhang
- & Sabine Lévi
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Article
| Open AccessExtrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors
Atypical antipsychotics show reduced extrapyramidal side effects compared to first generation drugs. Here the authors use time-resolved FRET to measure binding kinetics, and show that side effects correlate with drug association rates to the D2 receptor, while dissociation rates correlate with prolactin elevation.
- David A. Sykes
- , Holly Moore
- & Steven J. Charlton
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Article
| Open AccessNeurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism
How neurons and neuronal activity regulate astrocyte functions is poorly understood. Haselet al. identify two large groups of astrocytic genes that are regulated by neuronal contact and synaptic activity respectively, with distinct roles in astrocytic function; interestingly, many of these genes are dysregulated in neurodegeneration.
- Philip Hasel
- , Owen Dando
- & Giles E. Hardingham
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Article
| Open AccessAstrocytic GABA transporter activity modulates excitatory neurotransmission
Astrocytes monitor and regulate both excitatory and inhibitory synaptic activity. Here, the authors identify a novel form of neuronal-glia communication, by which astrocytes detect rises in GABA via the GABA transporter GAT-3; this results in adenosine release that acts presynaptically to inhibit neural glutamatergic signalling.
- Kim Boddum
- , Thomas P. Jensen
- & Matthew C. Walker
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Article
| Open AccessOrexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons
Stress is a major cause of relapse to cocaine seeking behaviour. Tung et al. show that orexin mediates stress-induced reinstatement of cocaine seeking behaviour in mice by endocannabinoid-dependent disinhibition in the ventral tegmental area.
- Li-Wei Tung
- , Guan-Ling Lu
- & Lih-Chu Chiou
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Article
| Open AccessActivation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation
Striatal D1 and D2-receptor expressing neurons have been shown to have opposing effects on reward-related behaviours. Here the authors reveal that specific activation of both D1 and D2 neurons in the nucleus accumbens leads to increase in motivational drive in rodents.
- Carina Soares-Cunha
- , Barbara Coimbra
- & Ana J. Rodrigues
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Article
| Open AccessTargeting neurotransmitter receptors with nanoparticles in vivo allows single-molecule tracking in acute brain slices
Single quantum dot tracking is an established technique used in cultured neurons and organotypic brain slices. Here, the authors demonstrate in vivotargeting of dopamine receptors via ventricular injection of functionalized quantum dots and track single nanoparticle-receptors in acute rat brain slices.
- Juan A. Varela
- , Julien P. Dupuis
- & Laurent Groc
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Article
| Open AccessLoss of UBE3A from TH-expressing neurons suppresses GABA co-release and enhances VTA-NAc optical self-stimulation
Mesoaccumbal terminals within the VTA are known to co-release both GABA and dopamine, although the functional role of the former has yet to be determined. Here, the authors find that non-canonical GABA release is regulated by the E3-ubiquitin ligase, UBE3A, and enhances optogenetic self-stimulation.
- Janet Berrios
- , Alice M. Stamatakis
- & Benjamin D. Philpot