Bidirectional influence of sodium channel activation on NMDA receptor-dependent cerebrocortical neuron structural plasticity

Joju George, Daniel G. Baden, William H. Gerwick, Thomas F. Murray

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Neuronal activity regulates brain development and synaptic plasticity through N-methyl-D-aspartate receptors (NMDARs) and calcium-dependent signaling pathways. Intracellular sodium ([Na+]i) also exerts a regulatory influence on NMDAR channel activity, and [Na+] imay, therefore, function as a signaling molecule. In an attempt to mimic the influence of neuronal activity on synaptic plasticity, we used brevetoxin-2 (PbTx-2), a voltage-gated sodium channel (VGSC) gating modifier, to manipulate [Na+]i in cerebrocortical neurons. The acute application of PbTx-2 produced concentration-dependent increments in both intracellular [Na+] and [Ca2+]. Pharmacological evaluation showed that PbTx-2-induced Ca2+ influx primarily involved VGSC activation and NMDAR-mediated entry. Additionally, PbTx-2 robustly potentiated NMDA-induced Ca2+ influx. PbTx-2-exposed neurons showed enhanced neurite outgrowth, increased dendritic arbor complexity, and increased dendritic filopodia density. The appearance of spontaneous calcium oscillations, reflecting synchronous neuronal activity, was accelerated by PbTx-2 treatment. Parallel to this response, PbTx-2 increased cerebrocortical neuron synaptic density. PbTx-2 stimulation of neurite outgrowth, dendritic arborization, and synaptogenesis all exhibited bidirectional concentration-response profiles. This profile paralleled that of NMDA, which also produced bidirectional concentration-response profiles for neurite outgrowth and synaptogenesis. These data are consistent with the hypothesis that PbTx-2-enhanced neuronal plasticity involves NMDAR-dependent signaling. Our results demonstrate that PbTx-2 mimics activity-dependent neuronal structural plasticity in cerebrocortical neurons through an increase in [Na+]i, up-regulation of NMDAR function, and engagement of downstream Ca2+-dependent signaling pathways. These data suggest that VGSC gating modifiers may represent a pharmacologic strategy to regulate neuronal plasticity through NMDAR-dependent mechanisms.

Original languageEnglish
Pages (from-to)19840-19845
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number48
DOIs
StatePublished - Nov 27 2012

Fingerprint

Sodium Channels
N-Methyl-D-Aspartate Receptors
Neuronal Plasticity
Neurons
Voltage-Gated Sodium Channels
Calcium Signaling
N-Methylaspartate
brevetoxin 2
Pseudopodia
Up-Regulation
Sodium
Pharmacology

All Science Journal Classification (ASJC) codes

  • General

Cite this

Bidirectional influence of sodium channel activation on NMDA receptor-dependent cerebrocortical neuron structural plasticity. / George, Joju; Baden, Daniel G.; Gerwick, William H.; Murray, Thomas F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 48, 27.11.2012, p. 19840-19845.

Research output: Contribution to journalArticle

@article{bb0f1da2c89c42abb762e4d9309851db,
title = "Bidirectional influence of sodium channel activation on NMDA receptor-dependent cerebrocortical neuron structural plasticity",
abstract = "Neuronal activity regulates brain development and synaptic plasticity through N-methyl-D-aspartate receptors (NMDARs) and calcium-dependent signaling pathways. Intracellular sodium ([Na+]i) also exerts a regulatory influence on NMDAR channel activity, and [Na+] imay, therefore, function as a signaling molecule. In an attempt to mimic the influence of neuronal activity on synaptic plasticity, we used brevetoxin-2 (PbTx-2), a voltage-gated sodium channel (VGSC) gating modifier, to manipulate [Na+]i in cerebrocortical neurons. The acute application of PbTx-2 produced concentration-dependent increments in both intracellular [Na+] and [Ca2+]. Pharmacological evaluation showed that PbTx-2-induced Ca2+ influx primarily involved VGSC activation and NMDAR-mediated entry. Additionally, PbTx-2 robustly potentiated NMDA-induced Ca2+ influx. PbTx-2-exposed neurons showed enhanced neurite outgrowth, increased dendritic arbor complexity, and increased dendritic filopodia density. The appearance of spontaneous calcium oscillations, reflecting synchronous neuronal activity, was accelerated by PbTx-2 treatment. Parallel to this response, PbTx-2 increased cerebrocortical neuron synaptic density. PbTx-2 stimulation of neurite outgrowth, dendritic arborization, and synaptogenesis all exhibited bidirectional concentration-response profiles. This profile paralleled that of NMDA, which also produced bidirectional concentration-response profiles for neurite outgrowth and synaptogenesis. These data are consistent with the hypothesis that PbTx-2-enhanced neuronal plasticity involves NMDAR-dependent signaling. Our results demonstrate that PbTx-2 mimics activity-dependent neuronal structural plasticity in cerebrocortical neurons through an increase in [Na+]i, up-regulation of NMDAR function, and engagement of downstream Ca2+-dependent signaling pathways. These data suggest that VGSC gating modifiers may represent a pharmacologic strategy to regulate neuronal plasticity through NMDAR-dependent mechanisms.",
author = "Joju George and Baden, {Daniel G.} and Gerwick, {William H.} and Murray, {Thomas F.}",
year = "2012",
month = "11",
day = "27",
doi = "10.1073/pnas.1212584109",
language = "English",
volume = "109",
pages = "19840--19845",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "48",

}

TY - JOUR

T1 - Bidirectional influence of sodium channel activation on NMDA receptor-dependent cerebrocortical neuron structural plasticity

AU - George, Joju

AU - Baden, Daniel G.

AU - Gerwick, William H.

AU - Murray, Thomas F.

PY - 2012/11/27

Y1 - 2012/11/27

N2 - Neuronal activity regulates brain development and synaptic plasticity through N-methyl-D-aspartate receptors (NMDARs) and calcium-dependent signaling pathways. Intracellular sodium ([Na+]i) also exerts a regulatory influence on NMDAR channel activity, and [Na+] imay, therefore, function as a signaling molecule. In an attempt to mimic the influence of neuronal activity on synaptic plasticity, we used brevetoxin-2 (PbTx-2), a voltage-gated sodium channel (VGSC) gating modifier, to manipulate [Na+]i in cerebrocortical neurons. The acute application of PbTx-2 produced concentration-dependent increments in both intracellular [Na+] and [Ca2+]. Pharmacological evaluation showed that PbTx-2-induced Ca2+ influx primarily involved VGSC activation and NMDAR-mediated entry. Additionally, PbTx-2 robustly potentiated NMDA-induced Ca2+ influx. PbTx-2-exposed neurons showed enhanced neurite outgrowth, increased dendritic arbor complexity, and increased dendritic filopodia density. The appearance of spontaneous calcium oscillations, reflecting synchronous neuronal activity, was accelerated by PbTx-2 treatment. Parallel to this response, PbTx-2 increased cerebrocortical neuron synaptic density. PbTx-2 stimulation of neurite outgrowth, dendritic arborization, and synaptogenesis all exhibited bidirectional concentration-response profiles. This profile paralleled that of NMDA, which also produced bidirectional concentration-response profiles for neurite outgrowth and synaptogenesis. These data are consistent with the hypothesis that PbTx-2-enhanced neuronal plasticity involves NMDAR-dependent signaling. Our results demonstrate that PbTx-2 mimics activity-dependent neuronal structural plasticity in cerebrocortical neurons through an increase in [Na+]i, up-regulation of NMDAR function, and engagement of downstream Ca2+-dependent signaling pathways. These data suggest that VGSC gating modifiers may represent a pharmacologic strategy to regulate neuronal plasticity through NMDAR-dependent mechanisms.

AB - Neuronal activity regulates brain development and synaptic plasticity through N-methyl-D-aspartate receptors (NMDARs) and calcium-dependent signaling pathways. Intracellular sodium ([Na+]i) also exerts a regulatory influence on NMDAR channel activity, and [Na+] imay, therefore, function as a signaling molecule. In an attempt to mimic the influence of neuronal activity on synaptic plasticity, we used brevetoxin-2 (PbTx-2), a voltage-gated sodium channel (VGSC) gating modifier, to manipulate [Na+]i in cerebrocortical neurons. The acute application of PbTx-2 produced concentration-dependent increments in both intracellular [Na+] and [Ca2+]. Pharmacological evaluation showed that PbTx-2-induced Ca2+ influx primarily involved VGSC activation and NMDAR-mediated entry. Additionally, PbTx-2 robustly potentiated NMDA-induced Ca2+ influx. PbTx-2-exposed neurons showed enhanced neurite outgrowth, increased dendritic arbor complexity, and increased dendritic filopodia density. The appearance of spontaneous calcium oscillations, reflecting synchronous neuronal activity, was accelerated by PbTx-2 treatment. Parallel to this response, PbTx-2 increased cerebrocortical neuron synaptic density. PbTx-2 stimulation of neurite outgrowth, dendritic arborization, and synaptogenesis all exhibited bidirectional concentration-response profiles. This profile paralleled that of NMDA, which also produced bidirectional concentration-response profiles for neurite outgrowth and synaptogenesis. These data are consistent with the hypothesis that PbTx-2-enhanced neuronal plasticity involves NMDAR-dependent signaling. Our results demonstrate that PbTx-2 mimics activity-dependent neuronal structural plasticity in cerebrocortical neurons through an increase in [Na+]i, up-regulation of NMDAR function, and engagement of downstream Ca2+-dependent signaling pathways. These data suggest that VGSC gating modifiers may represent a pharmacologic strategy to regulate neuronal plasticity through NMDAR-dependent mechanisms.

UR - http://www.scopus.com/inward/record.url?scp=84870320064&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870320064&partnerID=8YFLogxK

U2 - 10.1073/pnas.1212584109

DO - 10.1073/pnas.1212584109

M3 - Article

VL - 109

SP - 19840

EP - 19845

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 48

ER -