Inherited cortical HCN1 channel loss amplifies dendritic calcium electrogenesis and burst firing in a rat absence epilepsy model.
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.
Kole
Maarten H P
MH
Division of Neuroscience, John Curtin School of Medical Research, Australian National University, ACT, 0200, Canberra, Australia. maarten.kole@anu.edu.au
Bräuer
Anja U
AU
Stuart
Greg J
GJ
D000200:Action Potentials / Q000502:physiology; D000367:Age Factors; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D054815:Cyclic Nucleotide-Gated Cation Channels; D003712:Dendrites / Q000737:chemistry / Q000502:physiology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000235:genetics / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000032:analysis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000032:analysis; D008959:Models, Neurological; D018408:Patch-Clamp Techniques; D015221:Potassium Channels; D017966:Pyramidal Cells / Q000737:chemistry / Q000503:physiopathology*; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D013003:Somatosensory Cortex / Q000737:chemistry / Q000503:physiopathology*
D015220:Calcium Channels; D054815:Cyclic Nucleotide-Gated Cation Channels; C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D015221:Potassium Channels