Noradrenaline and the strength of glutamate signals in magnocellular neurosecretory cells: An obligatory role for neuronal and glial elements.

摘要

The release of noradrenaline (NA) into the paraventricular nucleus (PVN) and supraoptic nucleus (SON) is a critical step for enhanced magnocellular neuroendocrine cell (MNC) excitability in vivo. The adaptive responses mediated by these hypothalamic cell groups often require both rapid and sustained activation, yet clear synaptic mechanisms through which these demands might be met have not been explored. Here we tested whether NA elicited rapid and persistent changes in synaptic strength at glutamatergic synapses onto MNCs in male p21-28 Sprague-Dawley rats. Our results, based on the examination of miniature excitatory postsynaptic currents (mEPSCs), indicate that NA-induces three novel types of plasticity. First, we tested whether physiological activation of PKC via alpha1-adrenoceptors could remove inhibitory feedback by inactivating presynaptic metabotropic glutamate receptors (mGluRs). The results demonstrate that NA inactivates group III mGluRs, effectively priming these synapses such that subsequent activation is more efficacious. In the second study, prompted by the observation that NA elicits an enduring increase in the amplitude of mEPSCs, and supported by previous studies showing that NA is an activator of glial cells, that ATP is a ubiquitous gliotransmitter and that MNCs express Ca2+ permeable ATP-gated P2X receptors, we examined the contributions of glial-derived ATP to changes in postsynaptic efficacy. The NA induced increase in mEPSC amplitude exhibited enhanced postsynaptic responsiveness and was blocked both by a P2X receptor antagonist and by the withdrawal of glial processes from synapses following physiological dehydration. The gliotransmitter ATP therefore, contributes directly to postsynaptic efficacy. Finally, we examined the mechanisms responsible for large amplitude mEPSCs in response to NA, which are impervious to postsynaptic manipulations. Here, we tested whether NA recruits the synchronous release of multiple vesicles of glutamate. Large mEPSCs exhibited a putative multimodal amplitude histogram, were sensitive to ryanodine and were associated with an enhanced glutamate cleft concentration. These data suggest large mEPSCs result from the synchronous release of multiple vesicles via Ca2+ expulsion from intracellular stores. The observations presented here indicate that NA-mediated processes trigger rapid, robust responses at glutamate synapses that may be critical for contributing to the long-lasting excitability of MNCs necessary to meet physiological challenges.