High-Concentration Rapid Transients of Glutamate Mediate Neural-Glial Communication via Ectopic Release

Matsui, Kosuke; Jahr, Craig E.; Rubio, María E.

doi:10.1523/jneurosci.1927-05.2005

Cited by 130 publications

(127 citation statements)

References 49 publications

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“…Together with the recent finding that sensory input from whiskers induces mGluR-mediated astrocytic Ca 2+ responses at corresponding cortical sensory areas in vivo (38), these results show that physiological sensory stimulation is sufficient to induce volume transmission via high-affinity glutamate receptors in vivo. On the other hand, the EC 50 value of AMPAR (≈500 μM) (39) suggests that extrasynaptic AMPARs must be activated by spatiotemporally confined glutamate dynamics with submillimolar to millimolar concentrations at the close vicinity of synaptic clefts or ectopic glutamate release sites (10,(40)(41)(42)(43). Although such signals were difficult to resolve by the present EOS imaging method, the development of sister indicators of EOS with much lower affinity to glutamate and a method to control EOS localization may provide more information about the spatial profile of glutamate dynamics.…”

Section: Discussionmentioning

confidence: 99%

Imaging extrasynaptic glutamate dynamics in the brain

Okubo¹,

Sekiya²,

Namiki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

135

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Glutamate is the major neurotransmitter in the brain, mediating point-to-point transmission across the synaptic cleft in excitatory synapses. Using a glutamate imaging method with fluorescent indicators, we show that synaptic activity generates extrasynaptic glutamate dynamics in the vicinity of active synapses. These glutamate dynamics had magnitudes and durations sufficient to activate extrasynaptic glutamate receptors in brain slices. We also observed crosstalk between synapses-i.e., summation of glutamate released from neighboring synapses. Furthermore, we successfully observed that sensory input from the extremities induced extrasynaptic glutamate dynamics within the appropriate sensory area of the cerebral cortex in vivo. Thus, the present study clarifies the spatiotemporal features of extrasynaptic glutamate dynamics, and opens up an avenue to directly visualizing synaptic activity in live animals.synapse | spillover | fluorescence imaging | two-photon microscopy | in vivo G lutamate is the major excitatory neurotransmitter in the mammalian brain. The conventional view is that glutamate mediates synaptically confined point-to-point transmission at excitatory synapses. However, glutamate has also been suggested to escape from the synaptic cleft, generating extrasynaptic glutamate dynamics (often referred to as glutamate spillover) (1-4). Extrasynaptic glutamate dynamics has been implicated in the activation of extrasynaptic glutamate receptors via volume transmission to regulate a variety of important neural and glial functions including synaptic transmission (5, 6), synaptic plasticity (7), synaptic crosstalk (8-11), nonsynaptic neurotransmission (12, 13), neuronal survival (14), gliotransmitter release (15-17), and hemodynamic responses (18)(19)(20).Despite the immense potential physiological importance of glutamate spillover, the spatiotemporal dynamics of extrasynaptic glutamate concentration have been only inferred indirectly, and their characteristics remain elusive because of a lack of appropriate technology. Indeed, the magnitude and spatiotemporal distribution of extrasynaptic glutamate concentrations are the key determinants of physiological functions of glutamate spillover, and they are the essential factors for understanding extrasynaptic glutamate signaling. However, we have had to indirectly estimate the spatiotemporal dynamics of the glutamate spillover from its end effects mediated by glutamate receptors using electrophysiological and other means. To overcome this problem, we set out to image extrasynaptic glutamate dynamics in the brain.We developed glutamate indicators derived from the E (glutamate) optical sensor (EOS) (21). EOS is a hybrid-type fluorescent indicator consisting of the glutamate-binding domain of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit GluR2 and a fluorescent small molecule conjugated near the glutamate-binding pocket. EOS changes its fluorescence intensity upon binding of glutamate, for which it has both high affinity and high se...

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Section: Discussionmentioning

confidence: 99%

Imaging extrasynaptic glutamate dynamics in the brain

Okubo¹,

Sekiya²,

Namiki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

135

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“…Stimulus intensity was minimized to accomplish putative single RG fiber stimulation. For outside-out patch experiments, a theta glass flow-pipette mounted on a piezoelectric bimorph was used for rapid agonist application (Jonas, 1995;Matsui et al, 2005). Solution exchange time was measured after each experiment by rupturing the patch, and the junction currents across the open pipette tip were recorded (open tip response, 20 -80%; exchange time, 130 -220 s).…”

Section: Methodsmentioning

confidence: 99%

Mechanisms Underlying Signal Filtering at a Multisynapse Contact

Budisantoso¹,

Matsui²,

Kamasawa³

et al. 2012

J. Neurosci.

Self Cite

111

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Visual information must be relayed through the lateral geniculate nucleus before it reaches the visual cortex. However, not all spikes created in the retina lead to postsynaptic spikes and properties of the retinogeniculate synapse contribute to this filtering. To understand the mechanisms underlying this filtering process, we conducted electrophysiology to assess the properties of signal transmission in the Long-Evans rat. We also performed SDS-digested freeze-fracture replica labeling to quantify the receptor and transporter distribution, as well as EM reconstruction to describe the 3D structure. To analyze the impact of transmitter diffusion on the activity of the receptors, simulations were integrated. We identified that a large contributor to the filtering is the marked paired-pulse depression at this synapse, which was intensified by the morphological characteristics of the contacts. The broad presynaptic and postsynaptic contact area restricts transmitter diffusion two dimensionally. Additionally, the presence of multiple closely arranged release sites invites intersynaptic spillover, which causes desensitization of AMPA receptors. The presence of AMPA receptors that slowly recover from desensitization along with the high presynaptic release probability and multivesicular release at each synapse also contribute to the depression. These features contrast with many other synapses where spatiotemporal spread of transmitter is limited by rapid transmitter clearance allowing synapses to operate more independently. We propose that the micrometer-order structure can ultimately affect the visual information processing.

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“…To address this, we simulated glutamate diffusion within the synaptic cleft and calculated the glutamate concentration transient experienced by individual AMPARs located by the replica labeling. The open probabilities (Pos) of each AMPAR were calculated using the kinetic model of AMPARs (Wadiche and Jahr, 2001;Matsui et al, 2005), and the cell's total response to a vesicular release of glutamate was calculated by summation of the Pos of all AMPARs within the synapse (Fig. 5).…”

Section: Effect Of Microclusters Open Spaces and Release Locations mentioning

confidence: 99%

Input-Specific Intrasynaptic Arrangements of Ionotropic Glutamate Receptors and Their Impact on Postsynaptic Responses

Tarusawa¹,

Matsui²,

Budisantoso³

et al. 2009

J. Neurosci.

Self Cite

109

157

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To examine the intrasynaptic arrangement of postsynaptic receptors in relation to the functional role of the synapse, we quantitatively analyzed the two-dimensional distribution of AMPA and NMDA receptors (AMPARs and NMDARs, respectively) using SDS-digested freeze-fracture replica labeling (SDS-FRL) and assessed the implication of distribution differences on the postsynaptic responses by simulation. In the dorsal lateral geniculate nucleus, corticogeniculate (CG) synapses were twice as large as retinogeniculate (RG) synapses but expressed similar numbers ofAMPARs.Two-dimensionalviewsofreplicasrevealedthatAMPARsformmicroclustersinbothsynapsestoasimilarextent,resultinginlarger AMPAR-lacking areas in the CG synapses. Despite the broad difference in the AMPAR distribution within a synapse, our simulations based on the actual receptor distributions suggested that the AMPAR quantal response at individual RG synapses is only slightly larger in amplitude, less variable, and faster in kinetics than that at CG synapses having a similar number of the receptors. NMDARs at the CG synapses were expressed twice as many as those in the RG synapses. Electrophysiological recordings confirmed a larger contribution of NMDAR relative to AMPAR-mediated responses in CG synapses. We conclude that synapse size and the density and distribution of receptors have minor influences on quantal responses and that the number of receptors acts as a predominant postsynaptic determinant of the synaptic strength mediated by both the AMPARs and NMDARs.

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High-Concentration Rapid Transients of Glutamate Mediate Neural-Glial Communication via Ectopic Release

Cited by 130 publications

References 49 publications

Imaging extrasynaptic glutamate dynamics in the brain

Imaging extrasynaptic glutamate dynamics in the brain

Mechanisms Underlying Signal Filtering at a Multisynapse Contact

Input-Specific Intrasynaptic Arrangements of Ionotropic Glutamate Receptors and Their Impact on Postsynaptic Responses

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