Inherited cortical HCN1 channel loss amplifies dendritic calcium electrogenesis and burst firing in a rat absence epilepsy model.

Full Abstract

While idiopathic generalized epilepsies are thought to evolve from temporal highly synchronized oscillations between thalamic and cortical networks, their cellular basis remains poorly understood. Here we show in a genetic rat model of absence epilepsy (WAG/Rij) that a rapid decline in expression of hyperpolarization-activated cyclic-nucleotide gated (HCN1) channels (I(h)) precedes the onset of seizures, suggesting that the loss of HCN1 channel expression is inherited rather than acquired. Loss of HCN1 occurs primarily in the apical dendrites of layer 5 pyramidal neurons in the cortex, leading to a spatially uniform 2-fold reduction in dendritic HCN current throughout the entire somato-dendritic axis. Dual whole-cell recordings from the soma and apical dendrites demonstrate that loss of HCN1 increases somato-dendritic coupling and significantly reduces the frequency threshold for generation of dendritic Ca2+ spikes by backpropagating action potentials. As a result of increased dendritic Ca2+ electrogenesis a large population of WAG/Rij layer 5 neurons showed intrinsic high-frequency burst firing. Using morphologically realistic models of layer 5 pyramidal neurons from control Wistar and WAG/Rij animals we show that the experimentally observed loss of dendritic I(h) recruits dendritic Ca2+ channels to amplify action potential-triggered dendritic Ca2+ spikes and increase burst firing. Thus, loss of function of dendritic HCN1 channels in layer 5 pyramidal neurons provides a somato-dendritic mechanism for increasing the synchronization of cortical output, and is therefore likely to play an important role in the generation of absence seizures.

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Author information

Author/s: Kole, Maarten H P (MH); Bräuer, Anja U (AU); Stuart, Greg J (GJ);

Affiliation: Division of Neuroscience, John Curtin School of Medical Research, Australian National University, ACT, 0200, Canberra, Australia. maarten.kole(-atsign-)anu.edu.au

Journal and publication information

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

Journal: The Journal of physiology (J Physiol), published in England. (Language: eng)

Reference: 2007-Jan; vol 578 (issue Pt 2) : pp 507-25

Dates: Created 2007/01/15; Completed 2007/04/16; Revised 2008/11/20;

PMID: 17095562, status: MEDLINE (last retrieval date: 12/26/2008)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Action Potentials - physiology
Age Factors
Animals
Calcium Channels - metabolism
Calcium Signaling - physiology
Cyclic Nucleotide-Gated Cation Channels
Dendrites - chemistry; physiology
Disease Models, Animal
Electric Stimulation
Electroencephalography
Epilepsy, Absence - genetics; physiopathology
Excitatory Postsynaptic Potentials - physiology

Ion Channels - analysis; deficiency; genetics; physiology
Male
Membrane Potentials - physiology
Microtubule-Associated Proteins - analysis
Models, Neurological
Patch-Clamp Techniques
Potassium Channels
Pyramidal Cells - chemistry; physiopathology
Rats
Rats, Inbred Strains
Rats, Wistar
Somatosensory Cortex - chemistry; physiopathology

Associated Chemicals: Calcium Channels (0) ; Cyclic Nucleotide-Gated Cation Channels (0) ; HCN2 potassium channel (0) ; Ion Channels (0) ; Microtubule-Associated Proteins (0) ; Mtap2 protein, rat (0) ; Potassium Channels (0) ; hyperpolarization-activated cation channel (0)

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