Südkamp Nicolina, Shchyglo Olena, Manahan-Vaughan Denise
Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Bochum, Germany.
Front Aging Neurosci. 2024 May 20;16:1377085. doi: 10.3389/fnagi.2024.1377085. eCollection 2024.
Studies in rodent models have revealed that oligomeric beta-amyloid protein [Aβ (1-42)] plays an important role in the pathogenesis of Alzheimer's disease. Early elevations in hippocampal neuronal excitability caused by Aβ (1-42) have been proposed to be mediated via enhanced activation of GluN2B-containing N-methyl-D-aspartate receptors (NMDAR). To what extent GluN2A or GluN2B-containing NMDAR contribute to Aβ (1-42)-mediated impairments of hippocampal function in advanced rodent age is unclear. Here, we assessed hippocampal long-term potentiation (LTP) and neuronal responses 4-5 weeks after bilateral intracerebral inoculation of 8-15 month old GluN2A or GluN2B transgenic mice with oligomeric Aβ (1-42), or control peptide. Whole-cell patch-clamp recordings in CA1 pyramidal neurons revealed a more positive resting membrane potential and increased total spike time in GluN2A, but not GluN2B-hippocampi following treatment with Aβ (1-42) compared to controls. Action potential 20%-width was increased, and the descending slope was reduced, in Aβ-treated GluN2A, but not GluN2B hippocampi. Sag ratio was increased in Aβ-treated GluN2B-mice. Firing frequency was unchanged in wt, GluN2A, and GluN2Bhippocampi after Aβ-treatment. Effects were not significantly different from responses detected under the same conditions in wt littermates, however. LTP that lasted for over 2 h in wt hippocampal slices was significantly reduced in GluN2A and was impaired for 15 min in GluN2B-hippocampi compared to wt littermates. Furthermore, LTP (>2 h) was significantly impaired in Aβ-treated hippocampi of wt littermates compared to wt treated with control peptide. LTP induced in Aβ-treated GluN2A and GluN2B-hippocampi was equivalent to LTP in control peptide-treated transgenic and Aβ-treated wt animals. Taken together, our data indicate that knockdown of GluN2A subunits subtly alters membrane properties of hippocampal neurons and reduces the magnitude of LTP. GluN2B knockdown reduces the early phase of LTP but leaves later phases intact. Aβ (1-42)-treatment slightly exacerbates changes in action potential properties in GluN2A-mice. However, the vulnerability of the aging hippocampus to Aβ-mediated impairments of LTP is not mediated by GluN2A or GluN2B-containing NMDAR.
对啮齿动物模型的研究表明，寡聚β-淀粉样蛋白[Aβ(1 - 42)]在阿尔茨海默病的发病机制中起重要作用。有人提出，由Aβ(1 - 42)引起的海马神经元兴奋性早期升高是通过含GluN2B的N-甲基-D-天冬氨酸受体(NMDAR)的增强激活介导的。在老年啮齿动物中，含GluN2A或GluN2B的NMDAR在多大程度上导致Aβ(1 - 42)介导的海马功能损伤尚不清楚。在此，我们评估了在8 - 15月龄的含GluN2A或GluN2B的转基因小鼠双侧脑内接种寡聚Aβ(1 - 42)或对照肽4 - 5周后的海马长时程增强(LTP)和神经元反应。CA1锥体神经元的全细胞膜片钳记录显示，与对照组相比，用Aβ(1 - 42)处理后，GluN2A而非GluN2B海马中的静息膜电位更正，总峰时间增加。在Aβ处理的GluN2A而非GluN2B海马中，动作电位20%宽度增加，下降斜率减小。在Aβ处理的GluN2B小鼠中，凹陷比率增加。Aβ处理后，野生型、GluN2A和GluN2B海马中的放电频率未改变。然而，在相同条件下，这些效应与野生型同窝小鼠中检测到的反应没有显著差异。与野生型同窝小鼠相比，野生型海马切片中持续超过2小时的LTP在GluN2A中显著降低，在GluN2B海马中受损15分钟。此外，与用对照肽处理的野生型相比，Aβ处理的野生型同窝小鼠海马中的LTP(>2小时)显著受损。在Aβ处理的GluN2A和GluN2B海马中诱导的LTP与对照肽处理的转基因动物和Aβ处理的野生型动物中的LTP相当。综上所述，我们的数据表明，GluN2A亚基的敲低会微妙地改变海马神经元的膜特性并降低LTP的幅度。GluN2B敲低会降低LTP的早期阶段，但后期阶段保持完整。Aβ(1 - 42)处理会轻微加剧GluN2A小鼠动作电位特性的变化。然而，衰老海马对Aβ介导的LTP损伤的易感性不是由含GluN2A或GluN2B的NMDAR介导的。
