Use-dependent amplification of presynaptic Ca
            <sup>2+</sup>
            signaling by axonal ryanodine receptors at the hippocampal mossy fiber synapse

2011

Neuroscience Research

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Caffeine robustly enhances transmitter release from the hippocampal mossy fiber terminals, although it remains uncertain whether calcium mobilization through presynaptic ryanodine receptors mediates this enhancement. In this study, we adopted a selective adenosine A1 blocker to assess relative contribution of A1 receptors and ryanodine receptors in caffeine-induced synaptic enhancement. Application of caffeine further enhanced transmission at the hippocampal mossy fiber synapse even after full blockade of adenosine A1 receptors. This result suggests that caffeine enhances mossy fiber synaptic transmission by two distinct presynaptic mechanisms, i.e. removal of A1 receptor-mediated tonic inhibition and ryanodine receptor-mediated calcium release from intracellular stores. (Onodera, 1973;Erulkar and Rahamimoff, 1978). Recently, much evidence has been accumulated for the presence of ryanodine-sensitive store in presynaptic terminals and/or axons at the hippocampal mossy fiber synapse onto CA3 pyramidal cell (Liang et al., 2002;Lauri et al., 2003;Sharma et al., 2003). This notion was also supported by the finding that application of caffeine, drug acting on ryanodine receptor channels to release Ca 2+ from intracellular stores, strongly enhanced synaptic transmission at the hippocampal mossy fiber synapse (Shimizu et al., 2008). This result also suggests the presence of functional ryanodine receptors and possible CICR mechanisms may be involved in robust activity-dependent presynaptic plasticity characteristic for this synapse.However, caffeine is also known to block adenosine A1 receptors potently (Fredholm et al., 1999). It was found that extracellular adenosine acts on presynaptic A1 receptors and suppresses transmitter release via activation of G i/o (Dunwiddie and Hoffer, 1980). Therefore, it remains to be determined whether activation of ryanodine receptors, in addition to blocking A1 receptors, mediates the caffeine-induced enhancement at this synapse. In this study, we addressed this issue using a selective blocker of A1 receptor (8-cyclopentyl-1,3-dipropylxanthine; DPCPX) and an inhibitor of ryanodine receptor channels (ryanodine). We found that caffeine enhanced the hippocampal mossy fiber response even under full blockade of A1 receptors, and that the magnitude of enhancement was decreased in the presence of ryanodine. We also measured presynaptic Ca 2+ levels within mossy fiber terminals by fluorescence recording during application of DPCPX and caffeine. A part of this work was presented elsewhere in an abstract form (Sato and Kamiya, 2009).All experiments were performed according to the guidelines for the care and use of

mentioning

confidence: 49%

mentioning

confidence: 99%

Assessing the roles of presynaptic ryanodine receptors and adenosine receptors in caffeine-induced enhancement of hippocampal mossy fiber transmission

Sato

2011

Neuroscience Research

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“…Another interpretation is that the amplitude of mEPSCKA might fall below the threshold of detection in PSD-95 knockout mice (3 pA in the present study), since the amplitude of mEPSCKA is quite small (Shimizu et al, 2008). Thus, the reduction of mean frequency of mEPSCKA may not reflect the reduced transmitter release, but reflects the decrease of postsynaptic KARs in some population of synapses.…”

Section: ． Resultsmentioning

confidence: 67%

PSD-95 regulates synaptic kainate receptors at mouse hippocampal mossy fiber-CA3 synapses

Suzuki

2016

Neuroscience Research

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Kainate-type glutamate receptors (KARs) are the third class of ionotropic glutamate receptors whose activation leads to the unique roles in regulating synaptic transmission and circuit functions. In contrast to AMPA receptors (AMPARs), little is known about the mechanism of synaptic localization of KARs. PSD-95, a major scaffold protein of the postsynaptic density, is a candidate molecule that regulates the synaptic KARs. Although PSD-95 was shown to bind directly to KARs subunits, it has not been tested whether PSD-95 regulates synaptic KARs in intact synapses. Using PSD-95 knockout mice, we directly investigated the role of PSD-95 in the KARs-mediated components of synaptic transmission at hippocampal mossy fiber-CA3 synapse, one of the synapses with the highest density of KARs. Mossy fiber EPSCs consist of AMPA receptor (AMPAR)-mediated fast component and KAR-mediated slower component, and the ratio was significantly reduced in PSD-95 knockout mice. The size of KARs-mediated field EPSP reduced in comparison with the size of the fiber volley. Analysis of KARs-mediated miniature EPSCs also suggested reduced synaptic KARs. All the evidence supports critical roles of PSD-95 in regulating synaptic KARs

“…C57BL/6J mice of either sex were used in the present study, and were treated according to the guidelines for the care and use of laboratory animals of Hokkaido University. Transverse hippocampal slices 400 m thick were prepared from 14-to 21-d-old mice as described previously (Kamiya et al, 2002;Shimizu et al, 2008). Animals were anesthetized with ether and the brain was dissected out in an ice-cold sucrose solution containing the following (in mM): 40 NaCl, 25 NaHCO 3 , 10 glucose, 150 sucrose, 4 KCl, 1.25 NaH 2 PO 4 , 0.5 CaCl 2 , and 7 MgCl 2 .…”

Section: Methodsmentioning

confidence: 99%

Photochemical Inactivation Analysis of Temporal Dynamics of Postsynaptic Native AMPA Receptors in Hippocampal Slices

2012

J. Neurosci.

Postsynaptic expression of AMPA-type glutamate receptors (AMPAR) is more mobile than previously thought. Much evidence suggests that AMPAR are delivered from intracellular reserved pools to postsynaptic sites in a constitutive, as well as activity-dependent manner by exocytosis, lateral diffusion, or diffusional trapping. These notions were supported by optical monitoring of AMPAR subunits labeled with macromolecular tags such as GFP or Immunobeads, although it remains uncertain whether the mode and rate of synaptic delivery are similar to native "unlabeled" receptors. To reveal the real-time dynamics of native AMPAR in situ, photochemical inactivation of surface receptors using 6-azido-7-nitro-1,4-dihydroquinoxaline-2,3-dione (ANQX), a photoreactive AMPAR blocker, was adopted for acute hippocampal slices of mice. Because of the irreversible block due to cross-link formation between ANQX and surface AMPAR, recovery of EPSPs after photoinactivation reflects the time course of synaptic delivery of intracellular AMPAR. Brief UV illumination with fast application of ANQX resulted in persistent suppression of EPSPs for a prolonged period of up to 3 h, suggesting minimal synaptic delivery of AMPAR by exocytosis in the resting condition. Kinetic analysis of EPSP recovery clarified that the supply of postsynaptic AMPAR from the intracellular pool is dominated in the initial, but not in the later, phase of long-term potentiation (LTP). These results suggest that constitutive synaptic delivery is minimal in the resting condition at intact hippocampal synapses in a time scale of hours, while postsynaptic AMPAR are replaced with those in intracellular pools almost exclusively in an activity-dependent manner, typically shortly after LTP induction.