A misadventure of the correlation coefficient

The correlation coefficient gauges linear association between two variables. However, interpreting its value depends on the question at hand. This article argues that relying on the correlation coefficient may be irrelevant for many neuroscience research tasks. When the experimental dataset is contextually suitable for binning-averaging, other indicators of statistical association could prove more suitable

Multi-target action of β-alanine protects cerebellar tissue from ischemic damage

Acknowledgements The authors are grateful to Prof. Lora Heisler (University of Aberdeen, UK) for valuable suggestions on the research strategy and to the personnel of the military unit 7420 of the Armed Forces of Ukraine for their service and support. Funding This study was supported by the Wellcome Trust Principal Fellowship (212251_Z_18_Z), Medical Research Council (MR/W019752/1), and European Commission NEUROTWIN grant (857562) to DR.Peer reviewedPublisher PD

Sub-millisecond ligand probing of cell receptors with multiple solution exchange

The accurate knowledge of receptor kinetics is crucial to our understanding of cell signal transduction in general and neural function in particular. The classical technique of probing membrane receptors on a millisecond scale involves placing a recording micropipette with a membrane patch in front of a double-barrel (θ-glass) application pipette mounted on a piezo actuator. Driven by electric pulses, the actuator can rapidly shift the θ-glass pipette tip, thus exposing the target receptors to alternating ligand solutions. However, membrane patches survive for only a few minutes, thus normally restricting such experiments to a single-application protocol. In order to overcome this deficiency, we have introduced pressurized supply microcircuits in the θ-glass channels, thus enabling repeated replacement of application solutions within 10–15 s. this protocol, which has been validated in our recent studies and takes 20–60 min to implement, allows the characterization of ligand-receptor interactions with high sensitivity, thereby also enabling a powerful paired-sample statistical design

Do Astrocytes Respond to Dopamine?

Abstract. Astrocytes are now recognised as important contributors to synaptic transmission control. Dopamine is a key neuromodulator in the mammalian brain and establishing the potential extent of its actions involving astrocytes is vital to our overall understanding of brain function. Astrocyte membranes can express receptors for dopamine, as well as dopamine transporters, but the full effects of dopamine on astrocytic physiology are still uncertain and its mode of action controversial. Here we overview the developing field of astrocytedopamine interaction, focusing on how dopamine affects the pre-eminent astrocytic intracellular signalling messenger -Ca 2+ -and the available evidence for astrocyte-mediated effects of dopamine on neurons. We then discuss some of the methodological issues that need to be addressed to help move the field forward

Extracellular GABA waves regulate coincidence detection in excitatory circuits

Acknowledgements This study was supported by the Wellcome Trust Principal Fellowship (212251_Z_18_Z), ERC Advanced Grant (323113), and European Commission NEUROTWIN grant (857562) to DAR; University of Edinburgh Chancellor's Fellowship to SS.Peer reviewedPublisher PD

Rapid recycling of glutamate transporters on the astroglial surface.

Glutamate uptake by astroglial transporters confines excitatory transmission to the synaptic cleft. The efficiency of this mechanism depends on the transporter dynamics in the astrocyte membrane, which remains poorly understood. Here, we visualise the main glial glutamate transporter GLT1 by generating its pH-sensitive fluorescent analogue, GLT1-SEP. Fluorescence recovery after photobleaching-based imaging shows that 70-75% of GLT1-SEP dwell on the surface of rat brain astroglia, recycling with a lifetime of ~22 s. Genetic deletion of the C-terminus accelerates GLT1-SEP membrane turnover while disrupting its surface pattern, as revealed by single-molecule localisation microscopy. Excitatory activity boosts surface mobility of GLT1-SEP, involving its C-terminus, metabotropic glutamate receptors, intracellular Ca2+, and calcineurin-phosphatase activity, but not the broad-range kinase activity. The results suggest that membrane turnover, rather than lateral diffusion, is the main 'redeployment' route for the immobile fraction (20-30%) of surface-expressed GLT1. This finding reveals an important mechanism helping to control extrasynaptic escape of glutamate

Astrocytic GABA transporter activity modulates excitatory neurotransmission

Astrocytes are ideally placed to detect and respond to network activity. They express ionotropic and metabotropic receptors, and can release gliotransmitters. Astrocytes also express transporters that regulate the extracellular concentration of neurotransmitters. Here we report a previously unrecognized role for the astrocytic GABA transporter, GAT-3. GAT-3 activity results in a rise in astrocytic Na(+) concentrations and a consequent increase in astrocytic Ca(2+) through Na(+)/Ca(2+) exchange. This leads to the release of ATP/adenosine by astrocytes, which then diffusely inhibits neuronal glutamate release via activation of presynaptic adenosine receptors. Through this mechanism, increases in astrocytic GAT-3 activity due to GABA released from interneurons contribute to 'diffuse' heterosynaptic depression. This provides a mechanism for homeostatic regulation of excitatory transmission in the hippocampus

Retrograde Synaptic Signaling Mediated by K+ Efflux through Postsynaptic NMDA Receptors

SummarySynaptic NMDA receptors (NMDARs) carry inward Ca2+ current responsible for postsynaptic signaling and plasticity in dendritic spines. Whether the concurrent K+ efflux through the same receptors into the synaptic cleft has a physiological role is not known. Here, we report that NMDAR-dependent K+ efflux can provide a retrograde signal in the synapse. In hippocampal CA3-CA1 synapses, the bulk of astrocytic K+ current triggered by synaptic activity reflected K+ efflux through local postsynaptic NMDARs. The local extracellular K+ rise produced by activation of postsynaptic NMDARs boosted action potential-evoked presynaptic Ca2+ transients and neurotransmitter release from Schaffer collaterals. Our findings indicate that postsynaptic NMDAR-mediated K+ efflux contributes to use-dependent synaptic facilitation, thus revealing a fundamental form of retrograde synaptic signaling

Human neutrophils communicate remotely via calcium-dependent glutamate-induced glutamate release

Summary Neutrophils are white blood cells that are critical to acute inflammatory and adaptive immune responses. Their swarming-pattern behavior is controlled by multiple cellular cascades involving calcium-dependent release of various signaling molecules. Previous studies have reported that neutrophils express glutamate receptors and can release glutamate but evidence of direct neutrophil-neutrophil communication has been elusive. Here, we hold semi-suspended cultured human neutrophils in patch-clamp whole-cell mode to find that calcium mobilization induced by stimulating one neutrophil can trigger an N-methyl-D-aspartate (NMDA) receptor-driven membrane current and calcium signal in neighboring neutrophils. We employ an enzymatic-based imaging assay to image, in real time, glutamate release from neutrophils induced by glutamate released from their neighbors. These observations provide direct evidence for a positive-feedback inter-neutrophil communication that could contribute to mechanisms regulating communal neutrophil behavior

Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network

Mechanisms that entrain and pace rhythmic epileptiform discharges remain debated. Traditionally, the quest to understand them has focused on interneuronal networks driven by synaptic GABAergic connections. However, synchronized interneuronal discharges could also trigger the transient elevations of extracellular GABA across the tissue volume, thus raising tonic conductance (Gtonic) of synaptic and extrasynaptic GABA receptors in multiple cells. Here, we monitor extracellular GABA in hippocampal slices using patch-clamp GABA "sniffer" and a novel optical GABA sensor, showing that periodic epileptiform discharges are preceded by transient, region-wide waves of extracellular GABA. Neural network simulations that incorporate volume-transmitted GABA signals point to a cycle of GABA-driven network inhibition and disinhibition underpinning this relationship. We test and validate this hypothesis using simultaneous patch-clamp recordings from multiple neurons and selective optogenetic stimulation of fast-spiking interneurons. Critically, reducing GABA uptake in order to decelerate extracellular GABA fluctuations-without affecting synaptic GABAergic transmission or resting GABA levels-slows down rhythmic activity. Our findings thus unveil a key role of extrasynaptic, volume-transmitted GABA in pacing regenerative rhythmic activity in brain networks