Department of Anaesthesiology, Technische Universität München, Munich, Germany; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Department of Anaesthesiology, Technische Universität München, Munich, Germany.
Neuropharmacology. 2017 Sep 1;123:100-115. doi: 10.1016/j.neuropharm.2017.02.003. Epub 2017 Feb 4.
To elucidate whether a permanent reduction of the GluN2B subunit affects the pathology of Alzheimer's disease (AD), we cross-bred mice heterozygous for GluN2B receptors in the forebrain (hetGluN2B) with a mouse model for AD carrying a mutated amyloid precursor protein with the Swedish and Arctic mutation (mAPP) resulting in a hetGluN2B/mAPP transgenic. By means of voltage-sensitive dye imaging (VSDI) in the di-synaptic hippocampal pathway and the recording of field excitatory postsynaptic potentials (fEPSPs), hippocampal slices of all genotypes (WT, hetGluN2B, mAPP and hetGluN2B/mAPP, age 9-18 months) were tested for spatiotemporal activity propagation and long-term potentiation (LTP) induction. CA1-LTP induced by high frequency stimulation (HFS; 100 Hz/1s) was not different in all genotypes. Aβ (50 nM)-application reduced potentiation of fEPSP in WT and hetGluN2B/mAPP mice, LTP in mAPP and hetGluN2B mice was not affected. For VSDI a fast depolarization signal was evoked in the granule cell layer and propagation was analysed in hippocampal CA3 and CA1 region before and after theta stimulation (100pulses/5 Hz). LTP was not significantly different between all genotypes. In mAPP mice θ-stim produced an epileptiform activity reflected in a pronounced prolongation of the FDS compared to the other genotypes. In slices of hetGluN2B/mAPP and GluN2B mice, however, these parameters were similar to WT mice indicating a reversal effect of the attenuated GluN2B expression. The induction of a hetGluN2B mutation in the mAPP reversed some pathophysiological changes on hippocampal LTP and provide further evidence for the involvement of the glutamatergic system in AD and emphasize the GluN2B subunit as a potential target for AD treatment.
为了阐明 GluN2B 亚基的永久性减少是否会影响阿尔茨海默病（AD）的病理，我们将大脑前脑中 GluN2B 受体杂合的小鼠（hetGluN2B）与携带突变淀粉样前体蛋白的 AD 小鼠模型（mAPP）进行杂交，导致 hetGluN2B/mAPP 转基因。通过双突触海马通路的电压敏感染料成像（VSDI）和场兴奋性突触后电位（fEPSP）的记录，对所有基因型（WT、hetGluN2B、mAPP 和 hetGluN2B/mAPP，年龄 9-18 个月）的海马切片进行时空活动传播和长时程增强（LTP）诱导测试。高频刺激（HFS；100 Hz/1s）诱导的 CA1-LTP 在所有基因型中均无差异。WT 和 hetGluN2B/mAPP 小鼠中，Aβ（50 nM）应用降低了 fEPSP 的增强，而 mAPP 和 hetGluN2B 小鼠的 LTP 不受影响。对于 VSDI，在 theta 刺激（100 个脉冲/5 Hz）前后，在颗粒细胞层中诱发快速去极化信号，并在海马 CA3 和 CA1 区域中分析传播。所有基因型之间的 LTP 没有显著差异。在 mAPP 小鼠中，theta 刺激产生癫痫样活动，表现为与其他基因型相比，FDS 明显延长。然而，hetGluN2B/mAPP 和 GluN2B 小鼠的切片中，这些参数与 WT 小鼠相似，表明减弱的 GluN2B 表达具有逆转作用。hetGluN2B 突变在 mAPP 中的诱导逆转了海马 LTP 的一些病理生理变化，并进一步证明了谷氨酸能系统在 AD 中的参与，并强调了 GluN2B 亚基作为 AD 治疗的潜在靶点。
