Biology subjects

Jensen, T. P.

Publications and source records attributed to Jensen, T. P..

7 recordsLinked to original sources

bioRxiv2026

Sensory experience drives glutamate spillover, presynaptic LTP and functional connectome remodeling in the barrel cortex

Information handling and storage by neural circuits is thought to involve dynamic changes in the synaptic connectome, yet how this process unfolds at the level of individual synapses in vivo remains unclear. We took advantage of a well-defined thalamocortical anatomical framework to monitor identifiable individual synapses in barrel cortex during rhythmic whisker stimulation (RWS). Multiplexed ratiometric readouts from genetically targeted optical sensors showed that RWS-induced long-term potentiation (LTP) increased glutamate release per action potential in RWS-responsive axons while recruiting previously silent thalamocortical connections. Fast high-resolution imaging revealed pronounced inter-synaptic glutamate transients and global extracellular GABA waves triggered by brief RWS. LTP induction had no detectable effect on the evoked GABA signal but further enhanced glutamate crosstalk beyond thalamocortical synapses. Strikingly, neural-network simulations suggest that such volume-transmitted excitatory signals can improve associative memory retrieval in sparsely connected networks. Together, these findings uncover key plasticity features of the cortical synaptic connectome and point to a potential computational consequence of glutamate spillover for brain circuit function.

neuroscience↗

bioRxiv2022

Pliable synaptic fidelity and excitatory inter-synaptic crosstalk in the intact brain

Memory formation in neural circuits may involve changes in synaptic efficacy and in cell intrinsic excitability, yet how this process unfolds in the living brain has remained elusive. Here, we employed multiplexed imaging of genetically encoded indicators of glutamate and Ca2+ in mouse barrel cortex to detect increased fidelity coupled with reduced excitation of thalamocortical connections that undergo whisker-stimulation induced LTP. High-resolution imaging revealed that whisker stimuli trigger excitatory synaptic activity that generates extrasynaptic glutamate transients reaching the bulk of neighbouring synapses in the target cortical area. Our findings pave the way to understanding basic plasticity features of the synaptic connectome while revealing a significant component of volume-transmitted glutamatergic signalling among cells in the intact brain. One Sentence SummarySensory-stimulation LTP increases fidelity while reducing excitation at individual thalamocortical connections which generate spatially intersecting glutamate discharges

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bioRxiv2021

Extrasynaptic GABA waves underlie epileptiform rhythms in the hippocampal network

Mechanisms that entrain and drive rhythmic epileptiform discharges remain debated. Traditionally, this quest has been focusing on interneuronal networks driven by GABAergic connections that activate synaptic or extrasynaptic receptors. However, synchronised interneuronal discharges could also trigger a transient elevation of extracellular GABA across the tissue volume, thus raising tonic GABAA receptor conductance (Gtonic) in multiple cells. Here, we use patch-clamp GABA sniffer and optical GABA sensor to show that periodic epileptiform discharges are preceded by region-wide, rising waves of extracellular GABA. Neural network simulations that incorporate volume-transmitted GABA signals point to mechanistic principles underpinning this relationship. We validate this hypothesis using simultaneous patch-clamp recordings from multiple nerve cells, selective optogenetic stimulation of fast-spiking interneurons. Critically, we manipulate GABA uptake to suppress extracellular GABA waves but not synaptic GABAergic transmission, which shows a clear effect on rhythm generation. Our findings thus unveil a key role of extrasynaptic, volume-transmitted GABA actions in pacing regenerative rhythmic activity in brain networks.

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bioRxiv2020

Release probability increases towards distal dendrites boosting high-frequency signal transfer

Dendritic integration of synaptic inputs entangles their increased electrotonic attenuation at distal dendrites, which can be counterbalanced by the increased synaptic receptor density. However, during sustained network activity the influence of individual synapses depends on their release properties. How these properties are distributed along dendrites remains poorly understood. Here, we employed classical optical quantal analyses and a genetically encoded optical glutamate sensor in acute hippocampal slices to monitor release at CA3-CA1 synapses. We find that their release probability increases with greater distances from the soma. Similar-fidelity synapses tend to group together whereas release probability shows no trends regarding the within-branch position. Simulations with a realistic CA1 pyramidal cell hosting stochastic synapses suggest that the observed trends boost signal transfer fidelity, particularly at higher input frequencies. Because high-frequency bursting has been associated with learning, the release probability pattern we have found may play a key role in memory trace formation.

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bioRxiv2018

Astroglia withdraw from potentiated synapses boosting inter-synaptic cross-talk

Extrasynaptic actions of glutamate are limited by high-affinity transporters on perisynaptic astroglial processes (PAPs), which helps to maintain point-to-point transmission in excitatory circuits. Memory formation in the brain is associated with synaptic remodelling, but how this remodelling affects PAPs and therefore extrasynaptic glutamate actions is poorly understood. Here we used advanced imaging methods, in situ and in vivo, to find that a classical synaptic memory mechanism, long-term potentiation (LTP), triggers withdrawal of PAPs from potentiated synapses. Optical glutamate sensors combined with patch-clamp and 3D molecular localisation reveal that LTP induction thus prompts a spatial retreat of glial glutamate transporters, boosting glutamate spillover and NMDA receptor-mediated inter-synaptic cross-talk. The LTP-triggered PAP withdrawal involves NKCC1 transporters and the actin-controlling protein cofilin but does not depend on major Ca2+-dependent cascades in astrocytes. We have therefore uncovered a mechanism by which synaptic potentiation could alter signal handling by multiple nearby connections.

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bioRxiv2018

Multiplex imaging of quantal glutamate release and presynaptic Ca2+ at multiple synapses in situ

Information processing by brain circuits depends on Ca2+-dependent, stochastic release of the excitatory neurotransmitter glutamate. Recently developed optical sensors have enabled detection of evoked and spontaneous release at common glutamatergic synapses. However, monitoring synaptic release probability, its use-dependent changes, and its underpinning presynaptic machinery in situ requires concurrent, intensity-independent readout of presynaptic Ca2+ and glutamate release. Here, we find that the red-shifted Ca2+ indicator Cal-590 shows Ca2+-sensitive fluorescence lifetime, and employ it in combination with the novel green glutamate sensor SF-iGluSnFR variant to document quantal release of glutamate together with presynaptic Ca2+ concentration, in multiple synapses in an identified neural circuit. At the level of individual presynaptic boutons, we use multi-exposure and stochastic reconstruction procedures to reveal nanoscopic co-localisation of presynaptic Ca2+ entry and glutamate release, a fundamental unknown in modern neurobiology. This approach opens a new horizon in the quest to understand release machinery of central synapses.

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bioRxiv2018

A genetically encoded fluorescent sensor for in vivo imaging of GABA

Current techniques for monitoring GABA, the primary inhibitory neurotransmitter in vertebrates, cannot follow ephemeral transients in intact neural circuits. We applied the design principles used to create iGluSnFR, a fluorescent reporter of synaptic glutamate, to develop a GABA sensor using a protein derived from a previously unsequenced Pseudomonas fluorescens strain. Structure-guided mutagenesis and library screening led to a usable iGABASnFR ({Delta}F/Fmax ~ 2.5, Kd ~ 9 M, good specificity, adequate kinetics). iGABASnFR is genetically encoded, detects single action potential-evoked GABA release events in culture, and produces readily detectable fluorescence increases in vivo in mice and zebrafish. iGABASnFR enabled tracking of: (1) mitochondrial GABA content and its modulation by an anticonvulsant; (2) swimming-evoked GABAergic transmission in zebrafish cerebellum; (3) GABA release events during inter-ictal spikes and seizures in awake mice; and (4) GABAergic tone decreases during isoflurane anesthesia. iGABASnFR will permit high spatiotemporal resolution of GABA signaling in intact preparations.

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