Alzoubi Korem H, Aleisa Abdulaziz M, Alkadhi Karim A
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA.
J Mol Neurosci. 2005;27(3):337-46. doi: 10.1385/JMN:27:3:337.
Obese Zucker rat (OZR) is a genetic model of obesity with noninsulin-dependent diabetes and hypertension. The OZR exhibit hyperinsulinemia, hyperlipidmia, and high circulating glucocorticoid levels. We have shown previously that long-term potentiation (LTP) is impaired in the CA1 region of the hippocampus of OZR. In the present work, although electrophysiological recording from anesthetized OZR hippocampus showed impaired LTP in the CA1, an intact LTP was recorded in the dentate gyrus (DG) region of the hippocampus of the same OZR. Thus, LTP is differentially impaired in the CA1 compared with the DG region of OZR hippocampus. Immunoblotting was used to investigate the molecular mechanism responsible for impairment of LTP in the CA1 but not in the DG region. Analysis revealed reduction in the levels of phosphorylated calcium-dependent calmodulin kinase II (P-CaMKII) and total CaMKII in the CA1 region of OZR. However, in the DG region, reduction was observed only in the levels of total CaMKII, with no change in P-CaMKII levels. The ratio of P-CaMKII to total CaMKII was increased in the DG but not in the CA1 area of hippocampus of OZR. Although unchanged in the CA1, calcineurin levels were significantly reduced in the DG of OZR. These findings suggest that the DG might possess a compensatory mechanism whereby calcineurin levels are reduced to allow sufficient P-CaMKII to produce an apparently normal LTP in the DG area of OZR hippocampus.
肥胖 Zucker 大鼠（OZR）是一种具有非胰岛素依赖型糖尿病和高血压的肥胖遗传模型。OZR 表现出高胰岛素血症、高脂血症和循环糖皮质激素水平升高。我们之前已经表明，OZR 海马体 CA1 区的长时程增强（LTP）受损。在本研究中，尽管对麻醉的 OZR 海马体进行电生理记录显示 CA1 区的 LTP 受损，但在同一 OZR 海马体的齿状回（DG）区域记录到了完整的 LTP。因此，与 OZR 海马体的 DG 区域相比，CA1 区的 LTP 受损情况有所不同。采用免疫印迹法研究 CA1 区而非 DG 区 LTP 受损的分子机制。分析发现，OZR 的 CA1 区中磷酸化钙依赖性钙调蛋白激酶 II（P-CaMKII）和总 CaMKII 的水平降低。然而，在 DG 区域，仅观察到总 CaMKII 水平降低，P-CaMKII 水平没有变化。OZR 海马体 DG 区而非 CA1 区的 P-CaMKII 与总 CaMKII 的比值增加。尽管 CA1 区的钙调神经磷酸酶水平没有变化，但 OZR 的 DG 区中该酶水平显著降低。这些发现表明，DG 区可能具有一种补偿机制，通过降低钙调神经磷酸酶水平，使足够的 P-CaMKII 能够在 OZR 海马体的 DG 区产生明显正常的 LTP。
