A functional coupling between extrasynaptic NMDA receptors and A‐type K+ channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity
Year: 2014
Type: article
Abstract: Key points In hypothalamic magnocellular neurosecretory cells, activation of glutamate NMDA receptors leads to inhibition of the transient voltage‐gated A‐type K+ current (IA), in a Ca2+‐ and protein kinase C‐dependent manner. The negative NMDAR–IA functional coupling involves activation of extrasynaptic (e)NMDARs. The eNMDAR–IA coupling is engaged by endogenous extracellular glutamate, whose levels are controlled by astrocyte glutamate GLT1 transporters. The eNMDAR–IA coupling is enhanced during dehydration, a condition in which astrocyte GLT1 efficiency is blunted. The eNMDAR–IA coupling results in increased neuronal excitability and firing activity in magnocellular neurosecretory neurons. Taken together these studies support the concept that the eNMDAR–IA coupling is a powerful mechanism by which glutamate increases magnocellular neurosecretory excitability and firing activity. 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.
Source: The Journal of Physiology
Authors: Krishna Naskar, Javier E. Stern
Institution: Augusta University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1578846620