| Autor: |
Liu JJ; New York University Neuroscience Institute, New York University School of Medicine, New York, New York 10016., Eyring KW; New York University Neuroscience Institute, New York University School of Medicine, New York, New York 10016.; Neurogenetics Program, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095., König GM; Institute for Pharmaceutical Biology, University of Bonn, Bonn 53113, Germany., Kostenis E; Institute for Pharmaceutical Biology, University of Bonn, Bonn 53113, Germany., Tsien RW; New York University Neuroscience Institute, New York University School of Medicine, New York, New York 10016 richard.tsien@nyulangone.org. |
| Jazyk: |
angličtina |
| Zdroj: |
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2022 Oct 12; Vol. 42 (41), pp. 7707-7720. Date of Electronic Publication: 2022 Sep 08. |
| DOI: |
10.1523/JNEUROSCI.0921-22.2022 |
| Abstrakt: |
Oxytocin (OXT) and OXT receptor (OXTR)-mediated signaling control excitability, firing patterns, and plasticity of hippocampal CA2 pyramidal neurons, which are pivotal in generation of brain oscillations and social memory. Nonetheless, the ionic mechanisms underlying OXTR-induced effects in CA2 neurons are not fully understood. Using slice physiology in a reporter mouse line and interleaved current-clamp and voltage-clamp experiments, we systematically identified the ion channels modulated by OXT signaling in CA2 pyramidal cells (PYRs) in mice of both sexes and explored how changes in channel conductance support altered electrical activity. Activation of OXTRs inhibits an outward potassium current mediated by inward rectifier potassium channels ( I Kir ) and thus favoring membrane depolarization. Concomitantly, OXT signaling also diminishes inward current mediated by hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels ( I h ), providing a hyperpolarizing drive. The combined reduction in both I Kir and I h synergistically elevate the membrane resistance and favor dendritic integration while the membrane potential is restrained from quickly depolarizing from rest. As a result, the responsiveness of CA2 PYRs to synaptic inputs is highly sharpened during OXTR activation. Unexpectedly, OXTR signaling also strongly enhances a tetrodotoxin-resistant (TTX-R), voltage-gated sodium current that helps drive the membrane potential to spike threshold and thus promote rhythmic firing. This novel array of OXTR-stimulated ionic mechanisms operates in close coordination and underpins OXT-induced burst firing, a key step in CA2 PYRs' contribution to hippocampal information processing and broader influence on brain circuitry. Our study deepens our understanding of underpinnings of OXT-promoted social memory and general neuropeptidergic control of cognitive states. SIGNIFICANCE STATEMENT Oxytocin (OXT) plays key roles in reproduction, parenting and social and emotional behavior, and deficiency in OXT receptor (OXTR) signaling may contribute to neuropsychiatric disorders. We identified a novel array of OXTR-modulated ion channels that operate in close coordination to retune hippocampal CA2 pyramidal neurons, enhancing responsiveness to synaptic inputs and sculpting output. OXTR signaling inhibits both potassium conductance ( I Kir ) and mixed cation conductance ( I h ), engaging opposing influences on membrane potential, stabilizing it while synergistically elevating membrane resistance and electrotonic spread. OXT signaling also facilitates a tetrodotoxin-resistant (TTX-R) Na + current, not previously described in hippocampus (HP), engaged on further depolarization. This TTX-R current lowers the spike threshold and supports rhythmic depolarization and burst firing, a potent driver of downstream circuitry.
(Copyright © 2022 Liu et al.) |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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