| Abstract No.: | B-E2168 |
| Country: | Canada |
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| Title: | CONTROL OF SYNAPTICALLY GENERATED NEURAL ACTIVITY BY DENDRITICALLY RELEASED OPIOIDS |
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| Authors/Affiliations: | 1 Karl Iremonger*; 1 Jaideep Bains;
1 Hotchkiss Brain Institute, University of Calgary, AB, Canada
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| Content: | Objectives: Maintenance of fluid homeostasis is critical for an organisims survival and is controlled by vasopressin producing magnocellular neurosecretory cells (MNCs) in the paraventricular (PVN) and supraoptic nuclei of the hypothalamus. The release of vasopressin and the kappa opioid, dynorphin from the dendrites of these cells regulates their excitability and hence vasopressin secretion into the periphery. Surprisingly, the mechanism by which dynorphin inhibits synaptic transmission and its subsequent impact on synaptically generated spiking are relatively unknown.
Materials and Methods: We obtained whole-cell recordings from MNCs in brain slices containing the PVN of postnatal day 21-44 rats. In experiments where vasopressin cells were identified, transgenic rats that expressed enhanced green fluorescence protein under the vasopressin promoter were used. Excitatory postsynaptic currents (EPSCs) were evoked by extracellular stimulation with a glass microelectrode.
Results: Activation of kappa opioid receptors dramatically inhibited synaptically evoked firing in vasopressin MNCs. In control, short 50 Hz trains in voltage clamp evoked synchronous glutamate release during the train, followed by a prolonged barrage of asynchronous events after the train. We have previously shown that these asynchronous quanta are important in generating prolonged spiking in MNCs. Application of the kappa opioid agonist U69593 (1 μM, 5 min) inhibited evoked glutamate release with the effect being greater on the asynchronous component of release that followed the high frequency train. We next investigated the mechanisms of this inhibition. Application of U69593 increased the paired pulse ratio and inhibited mEPSC frequency without affecting amplitude, suggesting a presynaptic locus of inhibition. This decrease in glutamate releases was not mediated by inhibition of presynaptic calcium channels, adenylate cyclase/PKA pathways or fusion machinery. Instead, the inhibition was occluded by the non-specific potassium channel blocker 4-AP (2mM), but not other potassium channel blockers such as Ba2+ (0.6-1mM), alpha-dendrotoxin (100nM) or TEA (500µM).
Conclusion: Our results suggest that dendritically released dynorphin can dramatically reduce excitability by inhibiting evoked glutamate release via activation of a presynaptic potassium conductance. Because there is a differential inhibition of the synchronous versus asynchronous components of release during short high frequency trains, dendritically released dynorphin may not only decrease excitability but also alter the computational mode of the neuron.
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