Heuermann Robert J, Jaramillo Thomas C, Ying Shui-Wang, Suter Benjamin A, Lyman Kyle A, Han Ye, Lewis Alan S, Hampton Thomas G, Shepherd Gordon M G, Goldstein Peter A, Chetkovich Dane M
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.
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.
Neurobiol Dis. 2016 Jan;85:81-92. doi: 10.1016/j.nbd.2015.10.005. Epub 2015 Oct 14.
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.
失神发作见于多种人类癫痫类型，是由大脑皮层和丘脑之间广泛的同步反馈引起的，会导致短暂的意识丧失发作。基因啮齿动物模型对于研究这些癫痫发作的病理生理基础非常有价值。在此，我们确定含四肽重复序列的Rab8b相互作用蛋白（TRIP8b）基因敲除小鼠为失神癫痫的一种新模型，其脑电图（EEG）上有自发的棘波放电，这是失神发作的电图形标志。TRIP8b是超极化激活的环核苷酸门控（HCN）通道的一个辅助亚基，此前已被认为与失神发作的发病机制有关。与缺乏形成孔道的HCN通道亚基HCN2的小鼠不同，TRIP8b基因敲除小鼠表现出正常的心脏和运动功能以及较轻的癫痫发作表型。在评估失神发作的潜在神经回路时，我们发现TRIP8b基因敲除小鼠在投射到丘脑的皮层5b层神经元和丘脑中继神经元中HCN通道的表达和功能显著降低，但在丘脑网状核的抑制性神经元中功能保留。我们的结果扩展了TRIP8b的已知作用，并为TRIP8b和HCN通道在限制皮质-丘脑-皮质兴奋性方面的区域特异性功能提供了新的见解。
