Excitotoxic-mediated transcriptional decreases in HCN2 channel function increase network excitability in CA1.

Brendan Adams, Chris Reid, Damian Myers, Caroline Ng, Kim Powell, AM Phillips, Thomas Zheng, Terrence O'Brien, David Williams

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Changes in the conductance of the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channel that mediates Ih are proposed to contribute to increased network excitability. Synchronous neuronal burst activity is a good reflection of network excitability and can be generated in isolated hippocampal slice cultures by removing Mg2+ from the extracellular fluid. We demonstrate that Ih contributes to this activity by increasing both the frequency and duration of bursting events. Changes in HCN channel function are also implicated in altered seizure susceptibility. Short-term application of kainic acid (KA) is known to initiate long lasting changes in neuronal networks that result in seizures, and in slice cultures was found to alter HCN mRNA levels in an isoform and hippocampal sub-region specific manner. These changes correlate with the ability of each sub-region to develop synchronous burst activity following KA that we have previously reported. Specifically, a loss of synchronous activity in the CA3 correlated with an increase in HCN2 mRNA levels that normalized concomitantly with the restoration of CA3 burst activity 7 days post insult. In contrast, in CA1 an increase in synchronous burst duration correlated with a reduction in HCN2 mRNA levels and both changes were still evident for 7 days post insult. Lamotrigine, known to increase Ih, reversed the impact of KA on burst duration in CA1 at both time-points linking a transcriptional reduction in HCN2 function to increased burst duration.
Original languageEnglish
Pages (from-to)249-257
Number of pages9
JournalExperimental Neurology
Volume219
Issue number1
DOIs
Publication statusPublished - 2009

Fingerprint

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Kainic Acid
Messenger RNA
Seizures
Cyclic Nucleotides
Extracellular Fluid
Protein Isoforms

Cite this

Adams, Brendan ; Reid, Chris ; Myers, Damian ; Ng, Caroline ; Powell, Kim ; Phillips, AM ; Zheng, Thomas ; O'Brien, Terrence ; Williams, David. / Excitotoxic-mediated transcriptional decreases in HCN2 channel function increase network excitability in CA1. In: Experimental Neurology. 2009 ; Vol. 219, No. 1. pp. 249-257.
@article{ec223cca158644c78134a0e652df060b,
title = "Excitotoxic-mediated transcriptional decreases in HCN2 channel function increase network excitability in CA1.",
abstract = "Changes in the conductance of the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channel that mediates Ih are proposed to contribute to increased network excitability. Synchronous neuronal burst activity is a good reflection of network excitability and can be generated in isolated hippocampal slice cultures by removing Mg2+ from the extracellular fluid. We demonstrate that Ih contributes to this activity by increasing both the frequency and duration of bursting events. Changes in HCN channel function are also implicated in altered seizure susceptibility. Short-term application of kainic acid (KA) is known to initiate long lasting changes in neuronal networks that result in seizures, and in slice cultures was found to alter HCN mRNA levels in an isoform and hippocampal sub-region specific manner. These changes correlate with the ability of each sub-region to develop synchronous burst activity following KA that we have previously reported. Specifically, a loss of synchronous activity in the CA3 correlated with an increase in HCN2 mRNA levels that normalized concomitantly with the restoration of CA3 burst activity 7 days post insult. In contrast, in CA1 an increase in synchronous burst duration correlated with a reduction in HCN2 mRNA levels and both changes were still evident for 7 days post insult. Lamotrigine, known to increase Ih, reversed the impact of KA on burst duration in CA1 at both time-points linking a transcriptional reduction in HCN2 function to increased burst duration.",
keywords = "CA1, CA3, Epilepsy, HCN1, HCN2, Hippocampus, Ih, Kainic acid",
author = "Brendan Adams and Chris Reid and Damian Myers and Caroline Ng and Kim Powell and AM Phillips and Thomas Zheng and Terrence O'Brien and David Williams",
note = "Imported on 12 Apr 2017 - DigiTool details were: Journal title (773t) = Experimental Neurology. ISSNs: 0014-4886;",
year = "2009",
doi = "10.1016/j.expneurol.2009.05.030",
language = "English",
volume = "219",
pages = "249--257",
journal = "Neurodegeneration",
issn = "0014-4886",
publisher = "Academic Press",
number = "1",

}

Adams, B, Reid, C, Myers, D, Ng, C, Powell, K, Phillips, AM, Zheng, T, O'Brien, T & Williams, D 2009, 'Excitotoxic-mediated transcriptional decreases in HCN2 channel function increase network excitability in CA1.', Experimental Neurology, vol. 219, no. 1, pp. 249-257. https://doi.org/10.1016/j.expneurol.2009.05.030

Excitotoxic-mediated transcriptional decreases in HCN2 channel function increase network excitability in CA1. / Adams, Brendan; Reid, Chris; Myers, Damian; Ng, Caroline; Powell, Kim; Phillips, AM; Zheng, Thomas; O'Brien, Terrence; Williams, David.

In: Experimental Neurology, Vol. 219, No. 1, 2009, p. 249-257.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Excitotoxic-mediated transcriptional decreases in HCN2 channel function increase network excitability in CA1.

AU - Adams, Brendan

AU - Reid, Chris

AU - Myers, Damian

AU - Ng, Caroline

AU - Powell, Kim

AU - Phillips, AM

AU - Zheng, Thomas

AU - O'Brien, Terrence

AU - Williams, David

N1 - Imported on 12 Apr 2017 - DigiTool details were: Journal title (773t) = Experimental Neurology. ISSNs: 0014-4886;

PY - 2009

Y1 - 2009

N2 - Changes in the conductance of the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channel that mediates Ih are proposed to contribute to increased network excitability. Synchronous neuronal burst activity is a good reflection of network excitability and can be generated in isolated hippocampal slice cultures by removing Mg2+ from the extracellular fluid. We demonstrate that Ih contributes to this activity by increasing both the frequency and duration of bursting events. Changes in HCN channel function are also implicated in altered seizure susceptibility. Short-term application of kainic acid (KA) is known to initiate long lasting changes in neuronal networks that result in seizures, and in slice cultures was found to alter HCN mRNA levels in an isoform and hippocampal sub-region specific manner. These changes correlate with the ability of each sub-region to develop synchronous burst activity following KA that we have previously reported. Specifically, a loss of synchronous activity in the CA3 correlated with an increase in HCN2 mRNA levels that normalized concomitantly with the restoration of CA3 burst activity 7 days post insult. In contrast, in CA1 an increase in synchronous burst duration correlated with a reduction in HCN2 mRNA levels and both changes were still evident for 7 days post insult. Lamotrigine, known to increase Ih, reversed the impact of KA on burst duration in CA1 at both time-points linking a transcriptional reduction in HCN2 function to increased burst duration.

AB - Changes in the conductance of the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channel that mediates Ih are proposed to contribute to increased network excitability. Synchronous neuronal burst activity is a good reflection of network excitability and can be generated in isolated hippocampal slice cultures by removing Mg2+ from the extracellular fluid. We demonstrate that Ih contributes to this activity by increasing both the frequency and duration of bursting events. Changes in HCN channel function are also implicated in altered seizure susceptibility. Short-term application of kainic acid (KA) is known to initiate long lasting changes in neuronal networks that result in seizures, and in slice cultures was found to alter HCN mRNA levels in an isoform and hippocampal sub-region specific manner. These changes correlate with the ability of each sub-region to develop synchronous burst activity following KA that we have previously reported. Specifically, a loss of synchronous activity in the CA3 correlated with an increase in HCN2 mRNA levels that normalized concomitantly with the restoration of CA3 burst activity 7 days post insult. In contrast, in CA1 an increase in synchronous burst duration correlated with a reduction in HCN2 mRNA levels and both changes were still evident for 7 days post insult. Lamotrigine, known to increase Ih, reversed the impact of KA on burst duration in CA1 at both time-points linking a transcriptional reduction in HCN2 function to increased burst duration.

KW - CA1

KW - CA3

KW - Epilepsy

KW - HCN1

KW - HCN2

KW - Hippocampus

KW - Ih

KW - Kainic acid

U2 - 10.1016/j.expneurol.2009.05.030

DO - 10.1016/j.expneurol.2009.05.030

M3 - Article

VL - 219

SP - 249

EP - 257

JO - Neurodegeneration

JF - Neurodegeneration

SN - 0014-4886

IS - 1

ER -