Botterill J J, Brymer K J, Caruncho H J, Kalynchuk L E
Department of Psychology, University of Saskatchewan, Saskatoon, SK S7N 5A5, Canada.
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Epilepsy Behav. 2015 Jun;47:83-92. doi: 10.1016/j.yebeh.2015.04.046. Epub 2015 May 11.
Seizures dramatically increase the number of adult generated neurons in the hippocampus. However, it is not known whether this effect depends on seizures that originate in specific brain regions or whether it is nonspecific to seizure activity regardless of origin. We used kindling of different brain sites to address this question. Rats received 99 kindling stimulations of the basolateral amygdala, dorsal hippocampus, or caudate nucleus over a 6-week period. After kindling, we counted the number of adult generated hippocampal neurons that were birth-dated with the proliferative marker bromodeoxyuridine (BrdU) to evaluate cell proliferation and survival under conditions of repeated seizures. Next, we counted the number of doublecortin immunoreactive (DCX-ir) cells and evaluated their dendritic complexity to determine if limbic and nonlimbic seizures have differential effects on neuronal maturation. We also quantified hippocampal brain-derived neurotrophin factor (BDNF) protein levels using an ELISA kit and assessed memory performance using a hippocampal-dependent fear conditioning paradigm. We found that limbic, but not nonlimbic, seizures dramatically increased hippocampal cell proliferation and the number of hilar-CA3 ectopic granule cells. Further, limbic kindling promoted dendritic outgrowth of DCX-ir cells and the number of DCX-ir cells containing basal dendrites. Limbic kindling also enhanced BDNF protein levels throughout the entire hippocampus and impaired the retrieval of fear memories. Collectively, our results suggest a relationship between limbic seizures, neurogenesis, BDNF protein, and cognition.
癫痫发作会显著增加海马体中成年后生成的神经元数量。然而，尚不清楚这种效应是否取决于起源于特定脑区的癫痫发作，还是对癫痫活动是非特异性的，与起源无关。我们通过点燃不同脑区来解决这个问题。大鼠在6周内接受了99次对基底外侧杏仁核、背侧海马体或尾状核的点燃刺激。点燃后，我们对用增殖标记物溴脱氧尿苷（BrdU）标记出生时间的成年后生成的海马体神经元数量进行计数，以评估在反复癫痫发作条件下的细胞增殖和存活情况。接下来，我们对双皮质素免疫反应性（DCX-ir）细胞数量进行计数，并评估其树突复杂性，以确定边缘性和非边缘性癫痫发作对神经元成熟是否有不同影响。我们还使用酶联免疫吸附测定试剂盒对海马体脑源性神经营养因子（BDNF）蛋白水平进行定量，并使用依赖海马体的恐惧条件范式评估记忆表现。我们发现，边缘性癫痫发作而非非边缘性癫痫发作显著增加了海马体细胞增殖以及门区-CA3异位颗粒细胞的数量。此外，边缘性点燃促进了DCX-ir细胞的树突生长以及含有基底树突的DCX-ir细胞数量。边缘性点燃还提高了整个海马体的BDNF蛋白水平，并损害了恐惧记忆的提取。总的来说，我们的结果表明边缘性癫痫发作、神经发生、BDNF蛋白和认知之间存在关联。
