Department of Anesthesiology

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

TitleReduction of thalamic and cortical Ih by deletion of TRIP8b produces a mouse model of human absence epilepsy.
Publication TypeJournal Article
Year of Publication2016
AuthorsHeuermann RJ, Jaramillo TC, Ying S-W, Suter BA, Lyman KA, Han Y, Lewis AS, Hampton TG, Shepherd GMG, Goldstein PA, Chetkovich DM
JournalNeurobiol Dis
Volume85
Pagination81-92
Date Published2016 Jan
ISSN1095-953X
Abstract

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.

DOI10.1016/j.nbd.2015.10.005
Alternate JournalNeurobiol. Dis.
PubMed ID26459112
PubMed Central IDPMC4688217
Grant ListR01 NS059934 / NS / NINDS NIH HHS / United States
R21 NS067193 / NS / NINDS NIH HHS / United States
T32 MH067564 / MH / NIMH NIH HHS / United States