A functional coupling between extrasynaptic NMDA receptors and A-type K+ channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity.

Krishna Naskar, Javier E Stern

Index: J. Physiol. 592(Pt 13) , 2813-27, (2014)

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Abstract

Neuronal activity is controlled by a fine-tuned balance between intrinsic properties and extrinsic synaptic inputs. Moreover, neighbouring astrocytes are now recognized to influence a wide spectrum of neuronal functions. Yet, how these three key factors act in concert to modulate and fine-tune neuronal output is not well understood. Here, we show that in rat hypothalamic magnocellular neurosecretory cells (MNCs), glutamate NMDA receptors (NMDARs) are negatively coupled to the transient, voltage-gated A-type K(+) current (IA). We found that activation of NMDARs by extracellular glutamate levels influenced by astrocyte glutamate transporters resulted in a significant inhibition of IA. The NMDAR-IA functional coupling resulted from activation of extrasynaptic NMDARs, was calcium- and protein kinase C-dependent, and involved enhanced steady-state, voltage-dependent inactivation of IA. The NMDAR-IA coupling diminished the latency to the first evoked spike in response to membrane depolarization and increased the total number of evoked action potentials, thus strengthening the neuronal input/output function. Finally, we found a blunted NMDA-mediated inhibition of IA in dehydrated rats. Together, our findings support a novel signalling mechanism that involves a functional coupling between extrasynaptic NMDARs and A-type K(+) channels, which is influenced by local astrocytes. We show this signalling complex to play an important role in modulating hypothalamic neuronal excitability, which may contribute to adaptive responses during a sustained osmotic challenge such as dehydration. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.