title: Reduction of thalamic and cortical Ih by deletion of TRIP8b produces a mouse model of human absence epilepsy.
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.
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Ward Building, Room 10-201, Chicago, IL 60611, USA. Electronic address: r-heuermann@northwestern.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Heuermann
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Ward Building, Room 10-201, Chicago, IL 60611, USA. Electronic address: tom.jaramillo@utsouthwestern.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Jaramillo
authors.affiliation: C.V. Starr Laboratory for Molecular Neuropharmacology, Department of Anesthesiology, Weill Medical College of Cornell University, 1300 York Ave., Room A-1050, New York, New York 10021, USA. Electronic address: yingsw200@gmail.com.
authors.forename: Shui-Wang
authors.initials: SW
authors.lastname: Ying
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Ward Building, Room 10-201, Chicago, IL 60611, USA. Electronic address: ben.suter@gmail.com.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Suter
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Ward Building, Room 10-201, Chicago, IL 60611, USA. Electronic address: kyle-lyman@northwestern.edu.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Lyman
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Ward Building, Room 10-201, Chicago, IL 60611, USA. Electronic address: ye-han@northwestern.edu.
authors.forename: Ye
authors.initials: Y
authors.lastname: Han
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Ward Building, Room 10-201, Chicago, IL 60611, USA. Electronic address: alan.lewis@yale.edu.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Lewis
authors.affiliation: Mouse Specifics, Inc., 2 Central Street, Level 1 Suite 1, Framingham, MA 01701, USA. Electronic address: hampton@mousespecifics.com.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hampton
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Ward Building, Room 10-201, Chicago, IL 60611, USA. Electronic address: g-shepherd@northwestern.edu.
authors.forename: Gordon M G
authors.initials: GMG
authors.lastname: Shepherd
authors.affiliation: C.V. Starr Laboratory for Molecular Neuropharmacology, Department of Anesthesiology, Weill Medical College of Cornell University, 1300 York Ave., Room A-1050, New York, New York 10021, USA. Electronic address: pag2014@med.cornell.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Goldstein
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Ward Building, Room 10-201, Chicago, IL 60611, USA; Department of Physiology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Ward Building, Room 10-201, Chicago, IL 60611, USA. Electronic address: d-chetkovich@northwestern.edu.
authors.forename: Dane M
authors.initials: DM
authors.lastname: Chetkovich
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000503:physiopathology*; D004195:Disease Models, Animal; D004562:Electrocardiography; D000069280:Electrocorticography; D004567:Electrodes, Implanted; D004832:Epilepsy, Absence / Q000235:genetics / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D000074401:Peroxins; D045442:Rotarod Performance Test; D017384:Sequence Deletion; D013788:Thalamus / Q000503:physiopathology*; D046509:Tissue Culture Techniques
chemical_list: D008565:Membrane Proteins; D000074401:Peroxins; C501732:Pex5l protein, mouse
keywords: Absence epilepsy; HCN channels; I(h); Neocortex; TRIP8b; Thalamus