Pekcec Anton, Mühlenhoff Martina, Gerardy-Schahn Rita, Potschka Heidrun
Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilian-University, Koeniginstr 16, Munich, Germany.
Neurobiol Dis. 2007 Jul;27(1):54-66. doi: 10.1016/j.nbd.2007.04.002. Epub 2007 Apr 18.
Polysialylation is a posttranslational modification of the neural cell adhesion molecule (NCAM). In the adult brain, polysialylated NCAM (PSA-NCAM) is restricted to regions of neurogenesis and neuroplasticity, where PSA promotes plastic changes. Because a variety of plastic changes including neurogenesis have been suggested to be functionally involved in the pathophysiology of epilepsies, it is of specific interest to define the impact of the PSA-NCAM system on development and progression of this disease and associated comorbidities. Here, we studied the impact of transient enzymatic depolysialylation of NCAM on the pathophysiology in the amygdala kindling model, a chronic rodent model of temporal lobe epilepsy. The investigations focused on seizure-induced neurogenesis, seizure progression, and on the development of kindling-associated changes in behavior and cognition. Loss of PSA decreased the number of hippocampal newborn cells that incorporated BrdU during the kindling process and the number of new neurons that were ectopically located in the hilus. The persistence of basal dendrites has been suggested to be a hallmark of newborn granule cells in the epileptic brain. Loss of PSA increased the number of cells with persistent basal dendrites. The modification of the hippocampal cell proliferation rate and the fate of newborn neurons which occurred as a consequence of PSA removal did not affect the generation of a hyperexcitable kindled network or associated behavioral changes. Kindling progression was comparable in rats with and without removal of PSA. In contrast, loss of PSA increased acute seizure susceptibility as indicated by reduced seizure thresholds before kindling. The data indicate that hippocampal proliferation rates and ectoptic hilar newborn neurons are less critical for epileptic network generation. The PSA-NCAM system was not substantiated as a target for antiepileptogenic strategies. However, its impact on ectopic newborn neurons gives evidence that modulation of PSA-NCAM function may be a strategy to promote neuroregeneration in different central nervous system insults.
多唾液酸化是神经细胞黏附分子（NCAM）的一种翻译后修饰。在成人大脑中，多唾液酸化的NCAM（PSA-NCAM）局限于神经发生和神经可塑性区域，在这些区域中，PSA促进可塑性变化。由于包括神经发生在内的多种可塑性变化被认为在癫痫的病理生理学中具有功能作用，因此确定PSA-NCAM系统对该疾病及其相关合并症的发生和发展的影响具有特殊意义。在此，我们研究了NCAM的瞬时酶促去唾液酸化对杏仁核点燃模型（一种颞叶癫痫的慢性啮齿动物模型）病理生理学的影响。研究集中在癫痫发作诱导的神经发生、癫痫发作进展以及与点燃相关的行为和认知变化的发展。PSA的缺失减少了在点燃过程中掺入BrdU的海马新生细胞数量以及异位位于齿状回门区的新神经元数量。基底树突的持续存在被认为是癫痫大脑中新生颗粒细胞的一个标志。PSA的缺失增加了具有持续基底树突的细胞数量。由于PSA去除导致的海马细胞增殖率和新生神经元命运的改变并未影响过度兴奋的点燃网络的形成或相关的行为变化。有无PSA去除的大鼠的点燃进展相当。相比之下，如点燃前癫痫发作阈值降低所示，PSA的缺失增加了急性癫痫易感性。数据表明，海马增殖率和异位齿状回门区新生神经元对癫痫网络形成的重要性较低。PSA-NCAM系统未被证实是抗癫痫发生策略的靶点。然而，其对异位新生神经元的影响表明，调节PSA-NCAM功能可能是促进不同中枢神经系统损伤后神经再生的一种策略。
