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The Journal of Neuroscience, September 2, 2009, 29(35):10979-10988; doi:10.1523/JNEUROSCI.1531-09.2009

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Neurobiology of Disease
Loss of Dendritic HCN1 Subunits Enhances Cortical Excitability and Epileptogenesis

Zhuo Huang,¹ Matthew C. Walker,² and Mala M. Shah¹

¹Department of Pharmacology, The School of Pharmacy, University of London, London WC1N 1AX, United Kingdom, and ²UCL Institute of Neurology, University College London, London WC1N 3BG, United Kingdom

Correspondence should be addressed to Dr. Mala M. Shah, Department of Pharmacology, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK. Email: mala.shah{at}pharmacy.ac.uk

Hyperpolarization-activated cation nonselective 1 (HCN1) plasticity in entorhinal cortical (EC) and hippocampal pyramidal cell dendrites is a salient feature of temporal lobe epilepsy. However, the significance remains undetermined. We demonstrate that adult HCN1 null mice are more susceptible to kainic acid-induced seizures. After termination of these with an anticonvulsant, the mice also developed spontaneous behavioral seizures at a significantly more rapid rate than their wild-type littermates. This greater seizure susceptibility was accompanied by increased spontaneous activity in HCN1^–/– EC layer III neurons. Dendritic I_h in these neurons was ablated, too. Consequentially, HCN1^–/– dendrites were more excitable, despite having significantly more hyperpolarized resting membrane potentials (RMPs). In addition, the integration of EPSPs was enhanced considerably such that, at normal RMP, a 50 Hz train of EPSPs produced action potentials in HCN1^–/– neurons. As a result of this enhanced pyramidal cell excitability, spontaneous EPSC frequency onto HCN1^–/– neurons was considerably greater than that onto wild types, causing an imbalance between normal excitatory and inhibitory synaptic activity. These results suggest that dendritic HCN channels are likely to play a critical role in regulating cortical pyramidal cell excitability. Furthermore, these findings suggest that the reduction in dendritic HCN1 subunit expression during epileptogenesis is likely to facilitate the disorder.

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Received March 26, 2009; revised July 2, 2009; accepted July 18, 2009.

Correspondence should be addressed to Dr. Mala M. Shah, Department of Pharmacology, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK. Email: mala.shah{at}pharmacy.ac.uk

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