Åberg Elin, Holst Sarah, Neagu Alexandru, Ögren Sven Ove, Lavebratt Catharina
Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
PLoS One. 2013 Nov 14;8(11):e80497. doi: 10.1371/journal.pone.0080497. eCollection 2013.
Pregnant women with epilepsy have to balance maternal and fetal risks associated with uncontrolled seizures against the potential teratogenic effects from antiepileptic drugs (AEDs). Carbamazepine (CBZ) is among the four most commonly used AEDs for treatment of pregnant epileptic women. We previously reported that new-born children had a decreased head circumference after in utero CBZ exposure. This study investigates how prenatal exposure of CBZ influences the number of neurons in new-born and young mouse hippocampus, amygdala and cortex cerebri. Clinical studies describe inconclusive results on if prenatal CBZ treatment influences cognition. Here we investigate this issue in mice using two well characterized cognitive tasks, the passive avoidance test and the Morris water maze test. Prenatal exposure of CBZ reduced the number of neurons (NeuN-immunoreactive cells) in the new-born mouse hippocampus with 50% compared to non-exposed mice. A reduction of neurons (20%) in hippocampus was still observed when the animals were 5 weeks old. These mice also displayed a 25% reduction of neurons in cortex cerebri. Prenatal CBZ treatment did not significantly impair learning and memory measured in the passive avoidance test and in the Morris water maze. However, these mice displayed a higher degree of thigmotaxic behaviour than the control mice. The body weight of prenatally CBZ exposed five-week old mice were lower compared to control mice not exposed to CBZ (p = 0.001). In conclusion, prenatal exposure to CBZ reduces the number of neurons dramatically in areas important for cognition such as hippocampus and cortex, without severe impairments on learning and memory. These results are in line with some clinical studies, reporting that CBZ has minor negative effects on cognition. The challenge for future studies are to segment out what possible effects a reduction of neurons could have on different types of cognition, like intellectual ability and social interaction.
患有癫痫的孕妇必须在癫痫发作不受控制所带来的母体和胎儿风险与抗癫痫药物（AEDs）潜在的致畸作用之间进行权衡。卡马西平（CBZ）是治疗妊娠癫痫女性最常用的四种AEDs之一。我们之前报道过，子宫内接触CBZ的新生儿头围减小。本研究调查产前接触CBZ如何影响新生和幼年小鼠海马体、杏仁核和大脑皮质中的神经元数量。临床研究对于产前CBZ治疗是否影响认知的结果尚无定论。在此，我们使用两项特征明确的认知任务，即被动回避试验和莫里斯水迷宫试验，在小鼠中研究了这个问题。与未接触的小鼠相比，产前接触CBZ使新生小鼠海马体中的神经元数量（NeuN免疫反应性细胞）减少了50%。当动物5周大时，仍观察到海马体中的神经元减少了20%。这些小鼠大脑皮质中的神经元也减少了25%。产前CBZ治疗在被动回避试验和莫里斯水迷宫试验中测量的学习和记忆方面没有显著损害。然而，这些小鼠表现出比对照小鼠更高程度的趋触性。与未接触CBZ的对照小鼠相比，产前接触CBZ的5周龄小鼠体重更低（p = 0.001）。总之，产前接触CBZ会显著减少海马体和皮质等对认知重要区域的神经元数量，但对学习和记忆没有严重损害。这些结果与一些临床研究一致，这些研究报告称CBZ对认知有轻微负面影响。未来研究的挑战是区分神经元减少可能对不同类型的认知，如智力能力和社交互动，产生哪些可能的影响。
