Cornejo Brandon J, Mesches Michael H, Coultrap Steven, Browning Michael D, Benke Timothy A
Department of Pharmacology, University of Colorado, School of Medicine, Denver, CO 80262, USA.
Ann Neurol. 2007 May;61(5):411-26. doi: 10.1002/ana.21071.
The contribution of seizures to cognitive changes remains controversial. We tested the hypothesis that a single episode of neonatal seizures (sNS) on rat postnatal day (P) 7 permanently impairs hippocampal-dependent function in mature (P60) rats because of long-lasting changes at the synaptic level.
sNS was induced with subcutaneously injected kainate on P7. Learning, memory, mossy fiber sprouting, spine density, hippocampal synaptic plasticity, and glutamate receptor expression and subcellular distribution were measured at P60.
sNS selectively impaired working memory in a hippocampal-dependent radial arm water-maze task without inducing mossy fiber sprouting or altering spine density. sNS impaired CA1 hippocampal long-term potentiation and enhanced long-term depression. Subcellular fractionation and cross-linking, used to determine whether glutamate receptor trafficking underlies the alterations of memory and synaptic plasticity, demonstrated that sNS induced a selective reduction in the membrane pool of glutamate receptor 1 subunits. sNS induced a decrease in the total amount of N-methyl-D-aspartate receptor 2A and an increase in the primary subsynaptic scaffold, PSD-95.
These molecular consequences are consistent with the alterations in plasticity and memory caused by sNS at the synaptic level. Our data demonstrate the cognitive impact of sNS and associate memory deficits with specific alterations in glutamatergic synaptic function.
癫痫发作对认知变化的影响仍存在争议。我们检验了这样一个假设，即出生后第7天（P7）的新生大鼠单次癫痫发作（sNS）会因突触水平的长期变化而永久性损害成熟（P60）大鼠海马依赖性功能。
在P7时皮下注射海藻酸诱导sNS。在P60时测量学习、记忆、苔藓纤维发芽、棘密度、海马突触可塑性以及谷氨酸受体表达和亚细胞分布。
sNS在海马依赖性放射状臂水迷宫任务中选择性损害工作记忆，而不诱导苔藓纤维发芽或改变棘密度。sNS损害海马CA1区的长时程增强并增强长时程抑制。用于确定谷氨酸受体转运是否是记忆和突触可塑性改变基础的亚细胞分级分离和交联实验表明，sNS导致谷氨酸受体1亚基的膜池选择性减少。sNS导致N-甲基-D-天冬氨酸受体2A总量减少，初级突触后支架蛋白PSD-95增加。
这些分子结果与sNS在突触水平引起的可塑性和记忆改变一致。我们的数据证明了sNS的认知影响，并将记忆缺陷与谷氨酸能突触功能的特定改变联系起来。
