| Abstract No.: | C-B3024 |
| Country: | Canada |
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| Title: | RESOLVING THE CONTRIBUTION OF JUNCTIONAL VERSUS EXTRAJUNCTIONAL RECEPTORS TO SYNAPTIC TRANSMISSION AT GABAA SYNAPSES |
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| Authors/Affiliations: | 1 Dominic Boudreau*; 1 Gurgen Melkonyan; 2 Helmut Kroeger; 1 Yves De Koninck;
1 CRULRG, Québec, QC, Canada; 2 Universite Laval, Québec, QC, Canada
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| Content: | The subcellular distribution of receptors at central synapses has a critical impact on synaptic plasticity. GABAA receptors localization in rat superficial dorsal horn synapses may thus prove important in determining the excitability of the network relaying pain and sensory information to the brain.
We previously showed that in adult spinal lamina I inhibitory synapses, GABA fails to generate miniature inhibitory postsynaptic currents (mIPSCs) although GABA and glycine are coreleased. Given the slow kinetics of a benzodiazepine-revealed GABAA component to previously glycine-only mIPSCs at that synapse, we hypothesized that GABAA receptors were extrajunctional.
We reasoned that if the kinetics is affected by the distance between the receptor and the release site, modulating the diffusion coefficient of the extracellular milieu could affect the properties of mIPSCs. To test the hypothesis further, we conceived a computer model of a synapse in which were assessed the effect of variations in the diffusion coefficient and in the distance between receptors and release site. We then verified experimentally the effect of the extracellular environment viscosity on the kinetics of slow and fast rising GABAA -mediated mIPSCs, by adding dextran.
Monte Carlo simulations showed that the distance between the receptors and the release site is sufficient to explain the different rising kinetics of GABAA mIPSCs. Furthermore, simulations showed that changing the diffusion had a differential effect on the rising kinetics of synaptic events when these resulted from junctionally vs. extrajunctionally located receptors. Decreasing the diffusion coefficient cause an acceleration of the rise time of simulated mIPSCs involving junctional receptors, while it slowed the rise time of mIPSCs involving activation of extrajunctionally located receptors.
Patch clamp recordings from dorsal horn neurons in spinal cord slices showed that, addition of dextran to the bathing solution (to increase the viscosity of the extracellular milieu), had a differential effect on the rising kinetics of fast vs. slow rising GABAergic mIPSCs, in agreement with predictions from the simulations.
These results are consistent with an extrajunctional localization of GABAA receptors at adult spinal laminae I-II inhibitory synapses. Moreover, this approach presents a means to resolve the contribution of junctional versus extrajunctional receptors to synaptic events. Plasticity of this subcellular distribution may underlie functional changes at this spinal inhibitory synapse.
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