Loss of dendritic HCN1 subunits enhances cortical excitability and epileptogenesis.
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.
Huang
Zhuo
Z
Department of Pharmacology, The School of Pharmacy, University of London, London WC1N 1AX, United Kingdom.
Walker
Matthew C
MC
Shah
Mala M
MM
D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000172:deficiency* / Q000235:genetics*; D003712:Dendrites / Q000502:physiology*; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D051379:Mice; D018345:Mice, Knockout; D015221:Potassium Channels / Q000172:deficiency* / Q000235:genetics*; D021122:Protein Subunits / Q000172:deficiency* / Q000235:genetics*; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology
D054815:Cyclic Nucleotide-Gated Cation Channels; C578666:Hcn1 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D021122:Protein Subunits