Evans Madeline Collette, Dougherty Kelly Ann
Department of Biology, Rhodes College, 2000 N Parkway, Memphis, TN, 38112, USA.
Department of Biology, Rhodes College, 2000 N Parkway, Memphis, TN, 38112, USA.
Epilepsy Res. 2018 Sep;145:63-72. doi: 10.1016/j.eplepsyres.2018.05.014. Epub 2018 Jun 9.
Medial temporal lobe epilepsy (mTLE)-the most common form of focal epilepsy-is defined by recurrent partial seizures originating within the medial temporal lobe. Such seizures are commonly associated with the anterior hippocampus (as opposed to the posterior hippocampus), and refractory to the currently available anti-epileptic drugs (AED) for about one third of patients. Unfortunately, the mechanisms driving seizure generation and AED efficacy along the longitudinal hippocampal axis remain poorly understood. Recently, several groups investigating differences in excitability along the rodent longitudinal hippocampal axis have demonstrated that CA1 pyramidal neurons from the rodent ventral hippocampus (the rodent homolog of the human anterior hippocampus) are intrinsically more excitable than their dorsal counterparts (the rodent homolog of the human posterior hippocampus). This phenotypic difference is accompanied by significant differences in gene expression along the longitudinal hippocampal axis, which include gene products-such as voltage-gated sodium channel β-subunits-known to influence AED efficacy. Given this phenotypic heterogeneity, and the differential expression of gene products known to influence anti-epileptic drug efficacy, we sought to investigate the efficacy of the classical use-dependent sodium channel blocker, carbamazepine, in CA1 pyramidal neurons across the longitudinal hippocampal axis. Accordingly, we performed whole-cell current-clamp recordings on CA1 pyramidal neurons from acute hippocampal slices prepared from the dorsal and ventral hippocampus, and found that acute exposure to 100 μM carbamazepine induced a significantly greater suppression of repetitive firing for dorsal neurons relative to ventral neurons by inducing profound spike frequency adaptation (SFA). Moreover, we observed a small, but significant depolarization of resting membrane potential (RMP) for dorsal neurons (but not ventral neurons), following exposure to carbamazepine. Together, these observations demonstrate that carbamazepine's effect is concentrated in the dorsal hippocampus, which could provide meaningful insight into the side effect profile of carbamazepine (and related anti-epileptic drugs) in non-epileptic tissue, and inform future work investigating the mechanisms of carbamazepine resistance in epileptic tissue.
内侧颞叶癫痫（mTLE）——最常见的局灶性癫痫形式——由起源于内侧颞叶的反复发作性部分性癫痫发作所定义。此类癫痫发作通常与前海马体相关（与后海马体相对），并且约三分之一的患者对目前可用的抗癫痫药物（AED）耐药。不幸的是，沿海马体长轴驱动癫痫发作产生和AED疗效的机制仍知之甚少。最近，几个研究啮齿动物海马体长轴兴奋性差异的团队表明，来自啮齿动物腹侧海马体（人类前海马体的啮齿动物同源物）的CA1锥体神经元本质上比其背侧对应物（人类后海马体的啮齿动物同源物）更易兴奋。这种表型差异伴随着沿海马体长轴基因表达的显著差异，其中包括已知会影响AED疗效的基因产物，如电压门控钠通道β亚基。鉴于这种表型异质性以及已知影响抗癫痫药物疗效的基因产物的差异表达，我们试图研究经典的使用依赖性钠通道阻滞剂卡马西平在整个海马体长轴的CA1锥体神经元中的疗效。因此，我们对取自背侧和腹侧海马体的急性海马脑片的CA1锥体神经元进行了全细胞电流钳记录，发现急性暴露于100μM卡马西平会通过诱导深度的动作电位频率适应（SFA），相对于腹侧神经元，对背侧神经元的重复放电产生显著更大的抑制作用。此外，在暴露于卡马西平后，我们观察到背侧神经元（而非腹侧神经元）的静息膜电位（RMP）有小幅但显著的去极化。这些观察结果共同表明，卡马西平的作用集中在背侧海马体，这可以为卡马西平（及相关抗癫痫药物）在非癫痫组织中的副作用概况提供有意义的见解，并为未来研究癫痫组织中卡马西平耐药机制的工作提供参考。
