Extrasynaptic glutamate spillover in the hippocampus: evidence and implications

Kullmann, Dimitri M.; Asztély, Fredrik

doi:10.1016/s0166-2236(97)01150-8

Cited by 296 publications

(207 citation statements)

References 56 publications

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“…These results are in agreement with recent findings suggesting that, in the immature hippocampus, silent synapses containing an appreciable number of AMPA receptors appear silent because the peak of glutamate concentration in the synaptic cleft is too low to activate low-affinity AMPA receptors (25). Low levels of glutamate could arise either from spillover of neurotransmitter from neighboring terminals (34)(35)(36) and͞or by the trickle of neurotransmitter from a fusion pore as occurs in neuronal (37) or non-neuronal secretory cells (38)(39)(40). According to the spillover hypothesis, only high-affinity NMDA receptors, but not low-affinity AMPA receptors, would be activated by the low concentration of glutamate diffused from a neighboring synapse (35,41).…”

Section: Discussionsupporting

confidence: 92%

“…An enhanced probability of neurotransmitter release-after PPF, increased temperature, and CTZ-would allow glutamate to be released also locally close to the subsynaptic membrane so that its concentration would be high enough to activate both NMDA and AMPA receptors, thus converting silent synapses into functional ones. The higher percentage of silent synapses at 24°C rather than at 32°C, found in the present experiments, is also in favor of the spillover hypothesis (34,35). However, at physiological temperature, spillover would be limited by the higher rate of glutamate clearance from the extracellular space (34,36), and, therefore, the contribution of this mechanism should be minimal.…”

Section: Discussionsupporting

confidence: 49%

“…Low levels of glutamate could arise either from spillover of neurotransmitter from neighboring terminals (34)(35)(36) and͞or by the trickle of neurotransmitter from a fusion pore as occurs in neuronal (37) or non-neuronal secretory cells (38)(39)(40). According to the spillover hypothesis, only high-affinity NMDA receptors, but not low-affinity AMPA receptors, would be activated by the low concentration of glutamate diffused from a neighboring synapse (35,41). An enhanced probability of neurotransmitter release-after PPF, increased temperature, and CTZ-would allow glutamate to be released also locally close to the subsynaptic membrane so that its concentration would be high enough to activate both NMDA and AMPA receptors, thus converting silent synapses into functional ones.…”

Section: Discussionmentioning

confidence: 99%

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Silent synapses in the developing hippocampus: Lack of functional AMPA receptors or low probability of glutamate release?

Gasparini

Saviane

Voronin

et al. 2000

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

169

133

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At early developmental stages, silent synapses have been commonly found in different brain areas. These synapses are called silent because they do not respond at rest but are functional at positive membrane potentials. A widely accepted interpretation is that N-methyl-D-aspartate (NMDA) but not ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are functionally expressed on the subsynaptic membrane. Here we show that, in both CA3 and CA1 hippocampal regions, AMPA-mediated synaptic responses can be detected already at early stages of postnatal development. However, some synapses appear silent because of a very low probability of glutamate release. They can be converted into functional ones by factors that enhance release probability such as paired-pulse stimulation, increasing the temperature or cyclothiazide (CTZ), a drug that blocks AMPA receptor desensitization and increases transmitter release. Conversely, conducting synapses can be switched off by increasing the frequency of stimulation. Although we cannot exclude that ''latent AMPA receptors'' can become functional after activity-dependent processes, our results clearly indicate that, in the neonatal hippocampus, a proportion of glutamatergic synaptic connections are presynaptically rather than postsynaptically silent.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

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Silent synapses in the developing hippocampus: Lack of functional AMPA receptors or low probability of glutamate release?

Gasparini

Saviane

Voronin

et al. 2000

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

169

133

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“…A major difference between these approaches is that although only a single axon is stimulated in paired recordings, an unknown number of fibers is activated with extracellular stimulations. By stimulating a large number of fibers, transmitter "cross talk" or "pooling" may occur among the large number of activated boutons, changing the synaptic glutamate concentration waveform and resulting in a significant alteration in q when P r is increased (Barbour and Hausser, 1997;Kullmann and Asztely, 1998). Such a change in the transmitter concentration waveform may be interpreted as the consequence of multivesicular release.…”

Section: Discussionmentioning

confidence: 99%

Quantal Size Is Independent of the Release Probability at Hippocampal Excitatory Synapses

Biró¹,

Holderith²,

Nusser³

2005

J. Neurosci.

109

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Short-term synaptic plasticity changes the reliability of transmission during repetitive activation and allows different neuronal ensembles to encode distinct features of action potential trains. Identifying the mechanisms and the locus of expression of such plasticity is essential for understanding neuronal information processing. To determine the quantal parameters and the locus of alterations during short-term plasticity of cortical glutamatergic synapses, EPSCs were evoked in hippocampal oriens-alveus interneurons by CA1 pyramidal cells. The robust short-term facilitation of this connection allowed us to examine the transmission under functionally relevant but widely different release probability (P r ) conditions. Paired whole-cell recordings permitted the functional and post hoc morphological characterization of the synapses. To determine the quantal size (q), the P r , and the number of functional release sites (N F ), two independent quantal analysis methods were used. Light and electron microscopy were performed to identify the number of synaptic junctions (N EM ) between the recorded cells. The mean number of functional release sites (N F(f) ϭ 2.9 Ϯ 0.4; n ϭ 8) as inferred from a simple binomial model with no quantal variance agreed well with the mean of N EM (2.8 Ϯ 0.8; n ϭ 6), but N F(f) never matched N EM when they were compared in individual pairs; however, including quantal variance in the model improved the functional prediction of the structural data. Furthermore, an increased P r (4.8 Ϯ 0.8-fold) fully accounted for the marked short-term facilitation of EPSCs (5.0 Ϯ 0.7-fold), and q was independent of P r . Our results are consistent with the "one-release site, one-vesicle" hypothesis.

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“…While capturing the essence of synaptic transmission, this paradigm is an oversimplification. For example, transmitters such as GABA [1] and glutamate [2] can spill out of the synaptic cleft to have more diffuse and widespread actions than this classical model suggests. Under pathological conditions, transmitters and neurotransmitters, such as glutamate [3], can be released by the reversal of Na + -dependent concentrative transporters.…”

mentioning

confidence: 99%

Measurement of purine release with microelectrode biosensors

Dale

Frenguelli

2011

Purinergic Signalling

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Purinergic signalling departs from traditional paradigms of neurotransmission in the variety of release mechanisms and routes of production of extracellular ATP and adenosine. Direct real-time measurements of these purinergic agents have been of great value in understanding the functional roles of this signalling system in a number of diverse contexts. Here, we review the methods for measuring purine release, introduce the concept of microelectrode biosensors for ATP and adenosine and explain how these have been used to provide new mechanistic insight in respiratory chemoreception, synaptic physiology, eye development and purine salvage. We finish by considering the association of purine release with pathological conditions and examine the possibilities that biosensors for purines may one day be a standard part of the clinical diagnostic tool chest.Keywords Biosensor . Real-time measurement . Epilepsy . Stroke . Chemosensory mechanisms . DevelopmentThe need for real-time purine measurementThe traditional paradigm of synaptic transmission involves exocytotic release of transmitter from a defined presynaptic structure into the narrow gap of the synaptic cleft where it diffuses to activate receptors on the closely apposed postsynaptic membrane. Release is time-locked to the presynaptic action potential and results in the predictable occurrence of postsynaptic events on defined time scales. While capturing the essence of synaptic transmission, this paradigm is an oversimplification. For example, transmitters such as GABA [1] and glutamate [2] can spill out of the synaptic cleft to have more diffuse and widespread actions than this classical model suggests. Under pathological conditions, transmitters and neurotransmitters, such as glutamate [3], can be released by the reversal of Na + -dependent concentrative transporters.The purines, ATP and adenosine, depart from this paradigm even more comprehensively. ATP can indeed be released at synapses [4,5]. However, in the CNS, it seems that it acts mainly as a cotransmitter [6,7], and there are very few synapses where it acts as the principal transmitter. ATP is also released by glial cells [8,9] for the most part via exocytosis [10,11] but see [12]. However, ATP can also be released via a variety of channel-mediated mechanisms (for example, via gap junction hemichannels [13][14][15] and volume-activated channels [16,17]). Receptors for ATP are widespread throughout the CNS; yet, the cellular sources of ATP release to activate these receptors are not immediately obvious. In addition, although ATP can be broken down to ADP and further to adenosine, these breakdown products are themselves active at particular receptor subtypes.The routes for adenosine release and the cellular sources seem to be even more mysterious than those for ATP. For example, there is abundant evidence that adenosine can arise from the breakdown of previously released ATP [18].

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Extrasynaptic glutamate spillover in the hippocampus: evidence and implications

Cited by 296 publications

References 56 publications

Silent synapses in the developing hippocampus: Lack of functional AMPA receptors or low probability of glutamate release?

Silent synapses in the developing hippocampus: Lack of functional AMPA receptors or low probability of glutamate release?

Quantal Size Is Independent of the Release Probability at Hippocampal Excitatory Synapses

Measurement of purine release with microelectrode biosensors

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