Reduction of thalamic and cortical Ih by deletion of TRIP8b produces a mouse model of human absence epilepsy.

Heuermann RJ, Jaramillo TC, Ying SW, Suter BA, Lyman KA, Han Y, Lewis AS, Hampton TG, Shepherd GMG, Goldstein PA, Chetkovich DM
Neurobiol Dis. 2016 85: 81-92

PMID: 26459112 · PMCID: PMC4688217 · DOI:10.1016/j.nbd.2015.10.005

Absence seizures occur in several types of human epilepsy and result from widespread, synchronous feedback between the cortex and thalamus that produces brief episodes of loss of consciousness. Genetic rodent models have been invaluable for investigating the pathophysiological basis of these seizures. Here, we identify tetratricopeptide-containing Rab8b-interacting protein (TRIP8b) knockout mice as a new model of absence epilepsy, featuring spontaneous spike-wave discharges on electroencephalography (EEG) that are the electrographic hallmark of absence seizures. TRIP8b is an auxiliary subunit of the hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which have previously been implicated in the pathogenesis of absence seizures. In contrast to mice lacking the pore-forming HCN channel subunit HCN2, TRIP8b knockout mice exhibited normal cardiac and motor function and a less severe seizure phenotype. Evaluating the circuit that underlies absence seizures, we found that TRIP8b knockout mice had significantly reduced HCN channel expression and function in thalamic-projecting cortical layer 5b neurons and thalamic relay neurons, but preserved function in inhibitory neurons of the reticular thalamic nucleus. Our results expand the known roles of TRIP8b and provide new insight into the region-specific functions of TRIP8b and HCN channels in constraining cortico-thalamo-cortical excitability.

Copyright © 2015 Elsevier Inc. All rights reserved.

MeSH Terms (21)

Animals Blotting, Western Cerebral Cortex Disease Models, Animal Electrocardiography Electrocorticography Electrodes, Implanted Epilepsy, Absence Immunohistochemistry Male Membrane Potentials Membrane Proteins Mice, Knockout Motor Activity Neurons Patch-Clamp Techniques Peroxins Rotarod Performance Test Sequence Deletion Thalamus Tissue Culture Techniques

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