A functional coupling between extrasynaptic NMDA receptors and A-type K+ channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity.
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.
Department of Physiology, Medical College of Georgia, Georgia Regents University, Augusta, GA, 30912, USA.
Krishna
K
Naskar
Department of Physiology, Medical College of Georgia, Georgia Regents University, Augusta, GA, 30912, USA jstern@gru.edu.
Javier E
JE
Stern
D000200:Action Potentials; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D009490:Neurosecretory Systems / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D009997:Osmotic Pressure; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000502:physiology
D024642:Potassium Channels, Voltage-Gated; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D011493:Protein Kinase C; D002118:Calcium