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

Brendan E.L. Adams, Christopher A. Reid, Damian Myers, Caroline Ng, Kim Powell, A. Marie Phillips, Thomas Zheng, Terence J. O'Brien, David A. Williams

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12 Citations (Scopus)


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. Crown

Original languageEnglish
Pages (from-to)249-257
Number of pages9
JournalExperimental Neurology
Issue number1
Publication statusPublished - Sep 2009
Externally publishedYes


  • CA1
  • CA3
  • Epilepsy
  • HCN1
  • HCN2
  • Hippocampus
  • I
  • Kainic acid

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