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

Full 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.

Author information

Author/s: Adams, Brendan E L (BE); Reid, Christopher A (CA); Myers, Damian (D); Ng, Caroline (C); Powell, Kim (K); Phillips, A Marie (AM); Zheng, Thomas (T); O'Brien, Terence J (TJ); Williams, David A (DA);

Affiliation: Department of Physiology, The University of Melbourne, Australia.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Experimental neurology (Exp Neurol), published in United States. (Language: eng)

Reference: 2009-Sep; vol 219 (issue 1) : pp 249-57

Dates: Created 2009/08/18; Completed 2009/09/25;

PMID: 19500574, status: MEDLINE (last retrieved date: 9/25/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Action Potentials - drug effects; genetics
Animals
Biological Clocks - drug effects; genetics
Cortical Synchronization - drug effects
Epilepsy - genetics; metabolism; physiopathology
Excitatory Amino Acid Antagonists - pharmacology
Genetic Predisposition to Disease - genetics
Hippocampus - drug effects; metabolism
Ion Channels - genetics
Kainic Acid - pharmacology

Nerve Net - drug effects; metabolism
Neurotoxins - pharmacology
Organ Culture Techniques
RNA, Messenger - drug effects; metabolism
Rats
Rats, Sprague-Dawley
Synaptic Transmission - drug effects; genetics
Time Factors
Transcriptional Activation - drug effects; genetics
Triazines - pharmacology

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Excitatory Amino Acid Antagonists (0) ; HCN2 potassium channel (0) ; Ion Channels (0) ; Neurotoxins (0) ; RNA, Messenger (0) ; Triazines (0) ; Kainic Acid (487-79-6) ; lamotrigine (84057-84-1)

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