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This Article Full Text Full Text (PDF) Supplemental data All Versions of this Article: 578/2/507    most recent jphysiol.2006.122028v2 jphysiol.2006.122028v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kole, M. H.P. Articles by Stuart, G. J. Search for Related Content PubMed PubMed Citation Articles by Kole, M. H.P. Articles by Stuart, G. J. Related Collections Neuroscience

¹ Division of Neuroscience, John Curtin School of Medical Research, Australian National University, ACT, 0200, Canberra, Australia
² Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité Universitätsmedizin, Berlin, Philippstr. 12, D-10115 Berlin, Germany

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.

(Received 29 September 2006; accepted after revision 6 November 2006; first published online 9 November 2006)
Corresponding author M. H. P. Kole: Division of Neuroscience, John Curtin School of Medical Research, Australian National University, ACT, 0200, Canberra, Australia. Email: maarten.kole{at}anu.edu.au

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