Vilcaes Aldo Alejandro, Furlan Gabriela, Roth German A
Centro de Investigaciones en Química Biológica de Córdoba, Departamento de Química Biológica, Universidad Nacional de Córdoba, Argentina.
J Neurochem. 2009 Feb;108(4):881-90. doi: 10.1111/j.1471-4159.2008.05809.x.
Several pathological studies have revealed a prominent involvement of the cerebral cortex in patients with multiple sclerosis (MS). In order to better understand the events that lead to the progressive neuronal dysfunction in MS, herein we explore the contribution of the glutamatergic release in cerebral cortex synaptosomes isolated from rats with experimental autoimmune encephalomyelitis, an animal model reproducing many features of MS. We found that the Ca(2+)-dependent but not the Ca(2+)-independent glutamate release induced by KCl and 4-aminopyridine was significantly decreased during the acute stage of the disease. This inhibited release coincides with the onset of the clinical signs and after 24 h tends to recover the level of the control animals. The results also showed an inhibition of the glutamate release stimulated by ionomycin. When the animals were totally recovered from clinical signs, the neurotransmitter release stimulated by the different inductors was similar to the controls. Examination of the cytosolic Ca(2+) using fura-2-acetoxymethyl ester revealed that the inhibition of glutamate release could not be attributed to a reduction in voltage-dependent Ca(2+) influx. However, this inhibition was concomitant with a lower phosphorylation of synapsin I at P-site1. Our results show that the inhibition observed on the Ca(2+)-dependent neurotransmitter release from cerebral cortex synaptosomes in experimental autoimmune encephalomyelitis is specific and correlates with the beginning of the clinical disease. Moreover, they suggest an alteration in the metabolism of proteins involved in the vesicular glutamate release more than a deregulation in the influx of cytosolic Ca(2+).
多项病理学研究表明，多发性硬化症（MS）患者的大脑皮层受累明显。为了更好地理解导致MS患者神经元功能逐渐失调的事件，我们在此探究了从实验性自身免疫性脑脊髓炎大鼠分离出的大脑皮层突触体中谷氨酸能释放的作用，实验性自身免疫性脑脊髓炎是一种可重现MS多种特征的动物模型。我们发现，在疾病急性期，由氯化钾和4-氨基吡啶诱导的依赖钙（Ca(2+)）而非不依赖钙的谷氨酸释放显著减少。这种释放受抑制与临床症状的出现同时发生，24小时后趋于恢复到对照动物的水平。结果还显示，离子霉素刺激的谷氨酸释放受到抑制。当动物从临床症状中完全恢复后，不同诱导剂刺激的神经递质释放与对照相似。使用fura-2-乙酰氧甲酯检测胞质钙（Ca(2+)）发现，谷氨酸释放的抑制并非归因于电压依赖性钙（Ca(2+)）内流的减少。然而，这种抑制与突触结合蛋白I在P-site1处较低的磷酸化同时发生。我们的结果表明，在实验性自身免疫性脑脊髓炎中观察到的大脑皮层突触体依赖钙（Ca(2+)）的神经递质释放抑制是特异性的，且与临床疾病的开始相关。此外，这些结果表明，与胞质钙（Ca(2+)）内流失调相比，参与囊泡谷氨酸释放的蛋白质代谢发生了改变。
