Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
Biol Psychiatry. 2010 Mar 15;67(6):567-74. doi: 10.1016/j.biopsych.2009.11.008. Epub 2010 Jan 15.
Memory impairment is commonly associated with epilepsy, and the use of antiepileptic drugs (AEDs) causes additional neuropsychologic deficits that are of particular concern in learning-age children and elderly patients. The aim of this study was to investigate hippocampal synaptic plasticity and morphology as well as hippocampal-dependent memory in physiologic conditions and in a genetic model of epilepsy following chronic treatment with the widely used AED valproic acid (VPA).
Mice lacking the presynaptic scaffolding protein Bassoon were used as a model of epilepsy. Electrophysiologic recordings were used to analyze basal glutamatergic synaptic transmission, paired-pulse facilitation, and activity-dependent long-term potentiation (LTP) in the CA1 area. Dendritic morphology and spine density were analyzed, and glutamate-related signaling was investigated by Western blot analysis. Social transmission of food preference test was used to investigate nonspatial hippocampal memory.
VPA treatment significantly reduced seizures frequency and mortality in epileptic mice. Long-term potentiation was absent at CA1 synapses of untreated epileptic mutant mice that also showed significant dendritic abnormalities. Treatment with VPA rescued physiologic LTP but did not reverse morphological abnormalities and deficits in nonspatial hippocampal memory observed in mutant epileptic mice. Moreover, VPA was found to induce per se dendritic abnormalities and memory dysfunction in normal animals.
The impairment of hippocampal synaptic plasticity in epileptic mice, rescued by VPA treatment, might represent the mechanism underlying epilepsy-induced memory deficits. Moreover, the demonstration that VPA induces morphologic alterations and impairment in specific hippocampal-dependent memory task might explain the detrimental effects of antiepileptic treatment on cognition in human subjects.
记忆障碍通常与癫痫有关，而抗癫痫药物（AEDs）的使用会导致额外的神经心理缺陷，这在学习年龄段的儿童和老年患者中尤为令人关注。本研究旨在研究慢性使用广泛使用的 AED 丙戊酸（VPA）后，在生理条件下和遗传性癫痫模型中，海马突触可塑性和形态以及海马依赖性记忆。
使用缺乏突触前支架蛋白 Bassoon 的小鼠作为癫痫模型。电生理记录用于分析 CA1 区的基础谷氨酸能突触传递、成对脉冲易化和活性依赖性长时程增强（LTP）。分析树突形态和棘密度，并通过 Western blot 分析研究谷氨酸相关信号转导。通过社交食物偏好传递测试来研究非空间海马记忆。
VPA 治疗可显著降低癫痫小鼠的癫痫发作频率和死亡率。未经治疗的癫痫突变小鼠的 CA1 突触处不存在长时程增强，且表现出明显的树突异常。VPA 治疗可挽救生理 LTP，但不能逆转突变癫痫小鼠中观察到的形态异常和非空间海马记忆缺陷。此外，发现 VPA 本身可诱导正常动物的树突异常和记忆功能障碍。
癫痫小鼠海马突触可塑性的损伤可被 VPA 治疗挽救，这可能是癫痫引起记忆缺陷的机制。此外，证明 VPA 可引起形态改变和特定海马依赖性记忆任务的损害，可能解释了抗癫痫治疗对人类认知的有害影响。
