A functional coupling between extrasynaptic NMDA receptors and A‐type K+ channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity
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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 Ca 2+‐ 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. 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.
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Postsynaptic NMDARs regulate excitability and trigger somatodendritic oxytocin release.
“Postsynaptic NMDARs also regulate excitability48,49 and trigger somatodendritic oxytocin release47.”
From Neural circuitry for maternal oxytocin release induced by infant cries (2023) · cites this paper as [49]
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Neural circuitry for maternal oxytocin release induced by infant cries
Valtcheva, S., Issa, H. A., Bair-Marshall, C. J., Martin, K. A., Jung, K., Zhang, Y., Kwon, H.-B., & Froemke, R. C. (2023) · Nature · doi:10.1038/s41586-023-06540-4 · Cited by 115 · see citing works
- Authors
- Naskar, K., & Stern, J. E.
- Affiliations
- Augusta University (US)
- Corresponding author
- Stern, Javier E.
- ORCID
- Stern, Javier E.
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2014-06-04
- Volume
- 592
- Issue
- 13
- Pages
- 2813-2827
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC4221822
- OpenAlex
- W1578846620
- Cited by
- 28
- References
- 48
- Citations by year
- 2023: 2 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 6 · 2016: 2 · 2015: 3
- FWCI
- 1.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (NIH HL112225)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- extrasynaptic NMDA receptors, A-type potassium channels, GLT-1, neuronal excitability, dehydration, protein kinase C, calcium signaling, glutamate signalling, astrocyte-neuron interaction, action potential firing rate
- MeSH terms
- Action Potentials, Animals, Astrocytes, Calcium, Hypothalamus, Male, Neurons, Neurosecretory Systems, Osmotic Pressure, Protein Kinase C, Reaction Time, Synapses, Receptors, N-Methyl-D-Aspartate, Rats, Wistar, Glutamic Acid, Potassium Channels, Voltage-Gated, Rats
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