Glutamate receptor desensitization and its role in synaptic transmission

Trussell, Laurence O.; Fischbach, Gerald D.

doi:10.1016/0896-6273(89)90034-2

Cited by 448 publications

(289 citation statements)

References 44 publications

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“…Synaptic currents did not decay completely between pulses at stimulation frequencies higher than 50 Hz, and a significant shift of the baseline current developed. This introduced series resistance errors, and it might also have signaled the prolonged presence of glutamate in the synaptic cleft, which could lead to postsynaptic receptor desensitization (Trussell and Fischbach, 1989;Trussell et al, 1993). Therefore, we did not stimulate at frequencies higher than 50 Hz.…”

Section: Methodsmentioning

confidence: 99%

Modulation of Transmission during Trains at a Cerebellar Synapse

Kreitzer

Regehr

2000

J. Neurosci.

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Activity-dependent processes dynamically regulate synapses on the time scale of milliseconds to seconds. Here, we examine the factors governing synaptic strength during repetitive stimulation, both in control conditions and during presynaptic inhibition. Field recordings of presynaptic volleys, optical measurements of presynaptic calcium, and voltage-clamp recordings of postsynaptic currents were used to examine parallel fiber to Purkinje cell synapses in cerebellar brain slices at 34°C. In control conditions, regular stimulus trains (1-50 Hz) evoked up to a 250% peak synaptic enhancement, whereas during irregular stimulation, a threefold variability in EPSC amplitude was observed. When initial EPSC amplitudes were reduced by 50%, either by lowering external calcium or by activating adenosine A 1 or GABA B receptors, the peak enhancement during regular trains was 500%, and synaptic variability during irregular trains was nearly sixfold. By contrast, changes in fiber excitability and calcium influx per pulse were small during trains. Presynaptic calcium measurements indicated that by pulse 10, stimulusevoked calcium influx had increased by ϳ15%, which on the basis of the measured relationship between calcium influx and release corresponds to an EPSC enhancement of 50%. This enhancement was the same in all experimental conditions, even in the presence of N 6 -cyclopentyladenosine or baclofen, suggesting that repetitive stimulation does not relieve the G-protein inhibition of calcium channels by these modulators. Therefore, for our experimental conditions, changes in synaptic strength during trains are primarily attributable to residual calcium (Ca res )-dependent short-term plasticities, and the actions of neuromodulators during repetitive stimulation result from their inhibition of initial calcium influx and the resulting effects on Ca res and calcium-driven processes.

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Section: Methodsmentioning

confidence: 99%

Modulation of Transmission during Trains at a Cerebellar Synapse

Kreitzer

Regehr

2000

J. Neurosci.

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“…NMDA receptor channels have been shown to mediate the slow EPSCs in central neurons (Forsythe and Westbrook, 1988) and non-NMDA receptor channels have been shown to mediate the fast EPSCs (Hestrin et al, 1990). While step applications of glutamate evoke slow decremental current responses from NMDA receptor channels (Ascher et al, 1988;Mayer et al, 1989) similar stimuli evoke rapidly decaying current responses from non-NMDA receptor channels (Kiskin et al, 1986;Tang et al, 1989;Trussell and Fischbach, 1989;Thio et al, 199 1). The time dependent decay of the current response to a constant agonist concentration is known as desensitization (Thesleff, 1955).…”

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confidence: 99%

Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents

1993

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A distinctive characteristic of the AMPA subset of glutamate receptor channels is their remarkably rapid desensitization. A family of compounds, the benzothiadiazides, is described here that potently inhibit rapid glutamate receptor desensitization. The structure- activity relationships of these compounds are examined and the actions of cyclothiazide (CYZ), the most potent of these compounds, are described in detail. At the macroscopic level CYZ reduced rapid desensitization, enhancing the steady-state and peak current produced by 1 mM quisqualate with EC50 values of 14 and 12 microM, respectively, and shifted the quisqualate peak current concentration-response relation to the left. The slight outward rectification of the steady- state quisqualate current-voltage relationship was reduced by CYZ. At the microscopic level CYZ caused glutamate to induce long bursts of channel openings, and greatly increased the number of repeated openings. At 10 microM CYZ did not have measurable effects on the fast component of deactivation nor did it have statistically significant effects on the distribution of the faster components of glutamate- induced burst duration. In contrast, 10 microM CYZ increased the amplitude and significantly prolonged the duration of the spontaneous miniature EPSCs. The identification and characterization of this new family of gating modifiers may further facilitate the investigation into the mechanisms underlying rapid glutamate receptor desensitization and the physiological roles that it may serve.

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“…Glutamate is not rapidly degraded and will remain in the synaptic cleft until it is cleared by diffusion. Prolonged application of glutamate induces non-NMDA receptors to desensitize rapidly (Tang et al, 1989, 199 1;Trussell and Fischbach, 1989;Jonas and Sakmann, 1992;Colquhoun et al, 1992), suggesting that desensitization may contribute to synaptic decay. However, it has been estimated by Eccles and Jaeger (1958) for central synapses that because of diffusion only 10% of the peak neurotransmitter concentration remains after 500 msec, and a more recent study (Clements et al, 1992) suggests that 1 mM glutamate might be cleared from the synaptic cleft with a time constant of about 1.2 msec.…”

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confidence: 99%

Glutamate-activated currents in outside-out patches from spiny versus aspiny hilar neurons of rat hippocampal slices

1993

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The desensitization rate of non-NMDA glutamate receptors was investigated in outside-out membrane patches obtained from morphologically identified spiny “mossy cells” (SMCs) and aspiny hilar interneurons (AHIs) in young rat hippocampal slices. The fast application of a 1 mM step of L-glutamate for 50–100 msec in the presence of TTX and dizolcipine (MK-801) onto patches excised from these neurons produced large glutamate-activated currents (GACs) that decayed with a single or double exponential time course despite the continued presence of agonist. These desensitization rates of alpha- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate- sensitive receptors differed markedly between patches obtained from the two cell types. The fast time constant of desensitization in AHIs (n = 34) averaged 3.3 +/- 0.93 msec (mean +/- SD), while that of SMCs (n = 57) averaged 6.8 +/- 2.0 msec. Current-voltage relationships of the GACs did not differ between SMCs and AHIs, with comparable reversal potentials and no evidence of inward rectification. We also failed to observe significant Ca2+ permeability in either cell type. However, brief (< 1 msec) pulses of 1 mM glutamate produced rapidly decaying GACs with distinct kinetics in the two neuronal classes. Furthermore, analysis of the single glutamate-activated channel currents in outside- out patches from hilar neurons revealed a larger predominant single- channel current in AHIs versus SMCs. Lastly, we observed a greater sensitivity to cyclothiazide in SMCs versus AHIs, with half-maximal removal of desensitization being 90 mM and 200 mM, respectively. Taken together, these differences in GACs between SMCs and AHIs might indicate a functional correlate to the substantial heterogeneity in the molecular structure of glutamate receptor subunits or might be related to posttranslational modifications of these subunits, perhaps provided by the unique microenvironment in the spines covering SMCs.

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Glutamate receptor desensitization and its role in synaptic transmission

Cited by 448 publications

References 44 publications

Modulation of Transmission during Trains at a Cerebellar Synapse

Modulation of Transmission during Trains at a Cerebellar Synapse

Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents

Glutamate-activated currents in outside-out patches from spiny versus aspiny hilar neurons of rat hippocampal slices

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