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Jeffrey S Diamond

Publications and source records attributed to Jeffrey S Diamond.

10 recordsLinked to original sources
PubMed2006

Distinct perisynaptic and synaptic localization of NMDA and AMPA receptors on ganglion cells in rat retina.

At most excitatory synapses, AMPA and NMDA receptors (AMPARs and NMDARs) occupy the postsynaptic density (PSD) and contribute to miniature excitatory postsynaptic currents (mEPSCs) elicited by single transmitter quanta. Juxtaposition of AMPARs and NMDARs may be crucial for certain types of synaptic plasticity, although extrasynaptic NMDARs may also contribute. AMPARs and NMDARs also contribute to evoked EPSCs in retinal ganglion cells (RGCs), but mEPSCs are mediated solely by AMPARs. Previous work indicates that an NMDAR component emerges in mEPSCs when glutamate uptake is reduced, suggesting that NMDARs are located near the release site but perhaps not directly beneath in the PSD. Consistent with this idea, NMDARs on RGCs encounter a lower glutamate concentration during synaptic transmission than do AMPARs. To understand better the roles of NMDARs in RGC function, we used immunohistochemical and electron microscopic techniques to determine the precise subsynaptic localization of NMDARs in RGC dendrites. RGC dendrites were labeled retrogradely with cholera toxin B subunit (CTB) injected into the superior colliculus (SC) and identified using postembedding immunogold methods. Colabeling with antibodies directed toward AMPARs and/or NMDARs, we found that nearly all AMPARs are located within the PSD, while most NMDARs are located perisynaptically, 100-300 nm from the PSD. This morphological evidence for exclusively perisynaptic NMDARs localizations suggests a distinct role for NMDARs in RGC function.

Animals↗
PubMed2006

Fast neurotransmitter release triggered by Ca influx through AMPA-type glutamate receptors.

Feedback inhibition at reciprocal synapses between A17 amacrine cells and rod bipolar cells (RBCs) shapes light-evoked responses in the retina. Glutamate-mediated excitation of A17 cells elicits GABA (gamma-aminobutyric acid)-mediated inhibitory feedback onto RBCs, but the mechanisms that underlie GABA release from the dendrites of A17 cells are unknown. If, as observed at all other synapses studied, voltage-gated calcium channels (VGCCs) couple membrane depolarization to neurotransmitter release, feedforward excitatory postsynaptic potentials could spread through A17 dendrites to elicit 'surround' feedback inhibitory transmission at neighbouring synapses. Here we show, however, that GABA release from A17 cells in the rat retina does not depend on VGCCs or membrane depolarization. Instead, calcium-permeable AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs), activated by glutamate released from RBCs, provide the calcium influx necessary to trigger GABA release from A17 cells. The AMPAR-mediated calcium signal is amplified by calcium-induced calcium release (CICR) from intracellular calcium stores. These results describe a fast synapse that operates independently of VGCCs and membrane depolarization and reveal a previously unknown form of feedback inhibition within a neural circuit.

Amacrine Cells↗
PubMed2006

Astrocytes put down the broom and pick up the baton.

In this issue of Cell, Panatier et al. (2006) show that D-serine released by astrocytes, a type of glial cell in the brain, promotes NMDA receptor activity at synapses in the hypothalamus. These results confirm that glial cells participate in synaptic signaling and show that they can dictate the tenor of synaptic plasticity.

Animals↗
PubMed2006

Vesicle depletion and synaptic depression at a mammalian ribbon synapse.

We estimated the size of the readily releasable pool (RRP) of vesicles at a ribbon synapse in the rat retina by making paired voltage-clamp recordings from presynaptic rod bipolar cells (RBCs) and postsynaptic AII amacrine cells in an in vitro retinal slice preparation. The RRP at each active zone was estimated to constitute seven vesicles, in the range of estimated RRP sizes at conventional synapses. During sustained presynaptic Ca(2+) entry, the RRP could be released with a time constant of about 4 ms. This ribbon synapse exhibited pronounced paired-pulse depression (PPD), which was attributable primarily to vesicle depletion. Recovery from PPD was slow (tau approximately 4 s) but could be accelerated by increasing the duration of the depressing stimulus. The small RRP and very high release probability likely contribute to the transient characteristics of neurotransmission at RBC synapses.

Amacrine Cells↗
PubMed2005

Deriving the glutamate clearance time course from transporter currents in CA1 hippocampal astrocytes: transmitter uptake gets faster during development.

At many excitatory synapses, the neurotransmitter glutamate diffuses beyond the synaptic cleft to activate extrasynaptic targets. The extent and impact of such transmitter "spillover" on the processing capacity of neuronal networks are unclear, in part because it remains unknown how far transmitter diffuses from its point of release before being removed from the extracellular space by high-affinity glutamate transporters. Synaptically activated, transporter-mediated currents (STCs) recorded in hippocampal astrocytes provide an experimental measure of glutamate uptake, but the time course of the STC may be shaped, or "filtered," by other factors and therefore not represent a direct indication of clearance rate. Here, STCs were recorded from astrocytes in rat hippocampal slices under conditions in which uptake capacity was reduced and the STC decay reflected a slowed rate of glutamate clearance. The temporal characteristics of the filtering mechanisms were extracted from these responses, and the glutamate clearance time course in control conditions was derived. The results indicate that glutamate can be cleared from the extrasynaptic space within 1 ms. Clearance is fastest in adult neuropil, corresponding to a developmental increase in glial transporter expression. Synaptically released glutamate is taken up at the same rate as glutamate released via flash photolysis, indicating that the spatial location of transporters relative to the site of glutamate release does not affect the time course of clearance. Slower clearance in young animals would permit glutamate to diffuse greater distances, indicating a particularly important role for extrasynaptic receptors early in development.

Age Factors↗
PubMed2004

Coordinated multivesicular release at a mammalian ribbon synapse.

Traditional models of synaptic transmission hold that release sites within an active zone operate independently. Although the release of multiple vesicles (multivesicular release; MVR) from single active zones occurs at some central synapses, MVR is not thought to require coordination among release sites. Ribbon synapses seem to be optimized to release many vesicles over an extended period, but the dynamics of MVR at ribbon synapses is unknown. We examined MVR at a ribbon synapse in a retinal slice preparation using paired recordings from presynaptic rod bipolar and postsynaptic AII amacrine cells. When evoked release was highly desynchronized, discrete postsynaptic events were larger than quantal miniature excitatory postsynaptic currents (mEPSCs) but had the same time course. The amplitude of these multiquantal mEPSCs, which seem to arise from the essentially simultaneous release of multiple vesicles, was reduced by lowering release probability. The release synchrony reflected in these multivesicular events suggests that release within an active zone is coordinated during MVR.

Animals↗
PubMed2003

Sustained Ca2+ entry elicits transient postsynaptic currents at a retinal ribbon synapse.

Night (scotopic) vision is mediated by a distinct retinal circuit in which the light responses of rod-driven neurons are faster than those of the rods themselves. To investigate the dynamics of synaptic transmission at the second synapse in the rod pathway, we made paired voltage-clamp recordings from rod bipolar cells (RBCs) and postsynaptic AII and A17 amacrine cells in rat retinal slices. Depolarization of RBCs from -60 mV elicited sustained Ca2+ currents and evoked AMPA receptor (AMPAR)-mediated EPSCs in synaptically coupled amacrine cells that exhibited large, rapidly rising initial peaks that decayed rapidly to smaller, steady-state levels. The transient component persisted in the absence of feedback inhibition to the RBC terminal and when postsynaptic AMPA receptor desensitization was blocked with cyclothiazide, indicating that it reflects a time-dependent decrease in the rate of exocytosis from the presynaptic terminal. The EPSC waveform was similar when RBCs were recorded in perforated-patch or whole-cell configurations, but asynchronous release from RBCs was enhanced when the intraterminal Ca2+ buffer capacity was reduced. When RBCs were depolarized from -100 mV, inactivating, low voltage-activated (T-type channel-mediated) Ca2+ currents were evident. Although Ca2+ influx through T-type channels boosted vesicle release, as reflected by larger EPSCs, it did not make the EPSCs faster, indicating that activation of T-type channels is not necessary to generate a transient phase of exocytosis. We conclude that the time course of vesicle release from RBCs is inherently transient and, together with the fast kinetics of postsynaptic AMPARs, speeds transmission at this synapse.

Amacrine Cells↗
PubMed2003

Neuronal glutamate uptake Contributes to GABA synthesis and inhibitory synaptic strength.

Neurons must maintain a supply of neurotransmitter in their presynaptic terminals to fill synaptic vesicles. GABA is taken up into inhibitory terminals by transporters or is synthesized from glutamate by glutamic acid decarboxylase. Here we report that glutamate transporters supply GABAergic terminals in the hippocampus with glutamate, which is then used to synthesize GABA for filling synaptic vesicles. Glutamate transporter antagonists reduced IPSC and miniature IPSC (mIPSC) amplitudes, consistent with a reduction in the amount of GABA packaged into each synaptic vesicle. This reduction occurred rapidly and independently of synaptic activity, suggesting that modulation of vesicular GABA content does not require vesicle release and refilling. Raising extracellular glutamate levels increased mIPSC amplitudes by enhancing glutamate uptake and, consequently, GABA synthesis. These results indicate that neuronal glutamate transporters strengthen inhibitory synapses in response to extracellular glutamate. This modulation appears to occur under normal conditions and may constitute a negative feedback mechanism to combat hyperexcitability.

Amino Acid Transport System X-AG↗
PubMed2002

Synaptically released glutamate activates extrasynaptic NMDA receptors on cells in the ganglion cell layer of rat retina.

NMDA and AMPA receptors (NMDARs and AMPARs) are colocalized at most excitatory synapses in the CNS. Consequently, both receptor types are activated by a single quantum of transmitter and contribute to miniature and evoked EPSCs. However, in amphibian retina, miniature EPSCs in ganglion cell layer neurons are mediated solely by AMPARs, although both NMDARs and AMPARs are activated during evoked EPSCs. One explanation for this discrepancy is that NMDARs are located outside of the synaptic cleft and are activated only when extrasynaptic glutamate levels increase during coincident release from multiple synapses. Alternatively, NMDARs may be segregated at synapses that either are not spontaneously active or yield miniature EPSCs that are too small to detect. In this study, we examined excitatory, glutamatergic synaptic inputs to neurons in the ganglion cell layer of acute slices of rat retina. EPSCs, elicited by electrically stimulating presynaptic bipolar cells, exhibited both NMDAR- and AMPAR-mediated components. However, spontaneous EPSCs exhibited only an AMPAR-mediated component. The effects of low-affinity, competitive receptor antagonists indicated that NMDARs encounter less glutamate than AMPARs during an evoked synaptic response. Reducing glutamate uptake or changing the probability of release preferentially affected the NMDAR component in evoked EPSCs; reducing uptake revealed an NMDAR component in spontaneous EPSCs. These results indicate that NMDARs are located extrasynaptically and that glutamate transporters prevent NMDAR activation by a transmitter released from a single vesicle and limit their activation during evoked responses.

Animals↗