Clinical Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy.
Eur J Neurosci. 2013 Jan;37(1):150-62. doi: 10.1111/ejn.12032. Epub 2012 Oct 25.
Cortical dysplasias (CDs) include a spectrum of cerebral lesions resulting from cortical development abnormalities during embryogenesis that lead to cognitive disabilities and epilepsy. The experimental model of CD obtained by means of in utero administration of BCNU (1-3-bis-chloroethyl-nitrosurea) to pregnant rats on embryonic day 15 mimics the histopathological abnormalities observed in many patients. The aim of this study was to investigate the behavioural, electrophysiological and anatomical profile of BCNU-treated rats in order to determine whether cortical and hippocampal lesions can directly lead to cognitive dysfunction. The BCNU-treated rats showed impaired short-term working memory but intact long-term aversive memory, whereas their spontaneous motor activity and anxiety-like response were normal. The histopathological and immunohistochemical analyses, made after behavioural tests, revealed the disrupted integrity of neuronal populations and connecting fibres in hippocampus and prefrontal and entorhinal cortices, which are involved in memory processes. An electrophysiological evaluation of the CA1 region of in vitro hippocampal slices indicated a decrease in the efficiency of excitatory synaptic transmission and impaired paired pulse facilitation, but enhanced long-term potentiation (LTP) associated with hyperexcitability in BCNU-treated rats compared with controls. The enhanced LTP, associated with hyperexcitability, may indicate a pathological distortion of long-term plasticity. These findings suggest that prenatal developmental insults at the time of peak cortical neurogenesis can induce anatomical abnormalities associated with severe impairment of spatial working memory in adult BCNU-treated rats and may help to clarify the pathophysiological mechanisms of cognitive dysfunction that is often associated with epilepsy in patients with CD.
皮质发育不良（CDs）包括一系列由于胚胎发育过程中皮质发育异常而导致的脑损伤，从而导致认知障碍和癫痫。通过在胚胎第 15 天向怀孕的大鼠宫内给予 BCNU（1-3-双氯乙基-亚硝脲）来获得的 CD 实验模型模拟了许多患者中观察到的组织病理学异常。本研究旨在研究 BCNU 处理大鼠的行为、电生理和解剖学特征，以确定皮质和海马损伤是否会直接导致认知功能障碍。BCNU 处理的大鼠表现出短期工作记忆受损，但长期厌恶记忆完整，而其自发运动活动和焦虑样反应正常。行为测试后进行的组织病理学和免疫组织化学分析显示，海马体以及前额叶和内嗅皮质中的神经元群体和连接纤维的完整性受到破坏，这些区域参与记忆过程。对体外海马切片 CA1 区的电生理评估表明，与对照组相比，BCNU 处理的大鼠的兴奋性突触传递效率降低，并且成对脉冲易化受损，但长时程增强（LTP）增强，与兴奋过度有关。与兴奋过度相关的增强 LTP 可能表明长期可塑性的病理性扭曲。这些发现表明，在皮质神经发生高峰期的产前发育损伤会导致解剖学异常，从而导致成年 BCNU 处理大鼠的空间工作记忆严重受损，并且可能有助于阐明与 CD 患者中经常相关的认知功能障碍的病理生理机制。
