Loss of Dendritic HCN1 Subunits Enhances Cortical Excitability and Epileptogenesis

• Published in: The Journal of neuroscience 2009-09, Vol.29 (35), p.10979-10988
• Main Authors: Huang, Zhuo, Walker, Matthew C, Shah, Mala M
• Format: Article
• Language: English
• Subjects: Animals; Cerebral Cortex - cytology; Cerebral Cortex - physiology; Cyclic Nucleotide-Gated Cation Channels - deficiency; Cyclic Nucleotide-Gated Cation Channels - genetics; Dendrites - physiology; Epilepsy - genetics; Epilepsy - metabolism; Excitatory Postsynaptic Potentials - physiology; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Mice; Mice, Knockout; Potassium Channels - deficiency; Potassium Channels - genetics; Protein Subunits - deficiency; Protein Subunits - genetics; Pyramidal Cells - metabolism; Pyramidal Cells - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1531-09.2009

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 Ih 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.