Cain Stuart M, Tyson John R, Jones Karen L, Snutch Terrance P
Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 219-2185 East Mall, Vancouver, BC, Canada, V6T 1Z4.
Pflugers Arch. 2015 Jun;467(6):1367-82. doi: 10.1007/s00424-014-1549-4. Epub 2014 Jun 24.
Burst-firing in distinct subsets of thalamic relay (TR) neurons is thought to be a key requirement for the propagation of absence seizures. However, in the well-regarded Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model as yet there has been no link described between burst-firing in TR neurons and spike-and-wave discharges (SWDs). GAERS ventrobasal (VB) neurons are a specific subset of TR neurons that do not normally display burst-firing during absence seizures in the GAERS model, and here, we assessed the underlying relationship of VB burst-firing with Ih and T-type calcium currents between GAERS and non-epileptic control (NEC) animals. In response to 200-ms hyperpolarizing current injections, adult epileptic but not pre-epileptic GAERS VB neurons displayed suppressed burst-firing compared to NEC. In response to longer duration 1,000-ms hyperpolarizing current injections, both pre-epileptic and epileptic GAERS VB neurons required significantly more hyperpolarizing current injection to burst-fire than those of NEC animals. The current density of the Hyperpolarization and Cyclic Nucleotide-activated (HCN) current (Ih) was found to be increased in GAERS VB neurons, and the blockade of Ih relieved the suppressed burst-firing in both pre-epileptic P15-P20 and adult animals. In support, levels of HCN-1 and HCN-3 isoform channel proteins were increased in GAERS VB thalamic tissue. T-type calcium channel whole-cell currents were found to be decreased in P7-P9 GAERS VB neurons, and also noted was a decrease in CaV3.1 mRNA and protein levels in adults. Z944, a potent T-type calcium channel blocker with anti-epileptic properties, completely abolished hyperpolarization-induced VB burst-firing in both NEC and GAERS VB neurons.
丘脑中继（TR）神经元不同亚群中的爆发式放电被认为是失神发作传播的关键条件。然而，在备受认可的斯特拉斯堡遗传性失神癫痫大鼠（GAERS）模型中，尚未有关于TR神经元爆发式放电与棘波-慢波放电（SWD）之间联系的描述。GAERS腹侧基底（VB）神经元是TR神经元的一个特定亚群，在GAERS模型的失神发作期间通常不表现出爆发式放电，在此，我们评估了GAERS和非癫痫对照（NEC）动物之间VB爆发式放电与Ih和T型钙电流的潜在关系。响应200毫秒的超极化电流注入时，成年癫痫性而非癫痫前期的GAERS VB神经元与NEC相比，表现出爆发式放电受到抑制。响应持续时间更长的1000毫秒超极化电流注入时，癫痫前期和癫痫性GAERS VB神经元比NEC动物的神经元需要显著更多的超极化电流注入才能爆发式放电。发现GAERS VB神经元中超极化和环核苷酸激活（HCN）电流（Ih）的电流密度增加，Ih的阻断缓解了癫痫前期P15 - P20和成年动物中受到抑制的爆发式放电。作为支持，GAERS VB丘脑组织中HCN - 1和HCN - 3亚型通道蛋白的水平增加。在P7 - P9 GAERS VB神经元中发现T型钙通道全细胞电流减少，并且在成年动物中也注意到CaV3.1 mRNA和蛋白水平降低。Z944是一种具有抗癫痫特性的强效T型钙通道阻滞剂，完全消除了NEC和GAERS VB神经元中超极化诱导的VB爆发式放电。
