Neuronal Oscillations Laboratory, KI Alzheimer's Disease Research Center, NVS, Karolinska Institute, Stockholm, Sweden.
Neurobiol Aging. 2012 Sep;33(9):2046-61. doi: 10.1016/j.neurobiolaging.2011.07.013. Epub 2011 Sep 9.
Amyloid β (Aβ) peptides play a central role in the pathophysiology of Alzheimer's disease (AD). The cellular mechanisms underlying Aβ toxicity, however, are poorly understood. Here we show that Aβ(25-35) and Aβ(1-40) acutely and differentially affect the characteristics of 3 classes of medial septum (MS) neurons in mice. In glutamatergic neurons Aβ increases firing frequency and blocks the A- and the M-current (I(A) and I(M), respectively). While the I(A) block is similar in other MS neuron classes, the block of I(M) is specific to glutamatergic neurons. I(M) block and a simulated Aβ block mimic the Aβ-induced increase in spontaneous firing in glutamatergic neurons. Calcium imaging shows that under control conditions glutamatergic neurons rarely fire while nonglutamatergic neurons fire coherently at theta frequencies. Aβ increases the firing rate of glutamatergic neurons while nonglutamatergic neurons lose theta firing coherence. Our results demonstrate that Aβ-induced dysfunction of glutamatergic neurons via I(M) decrease diminishes MS rhythmicity, which may negatively affect hippocampal rhythmogenesis and underlie the memory loss observed in Alzheimer's disease.
淀粉样 β (Aβ) 肽在阿尔茨海默病 (AD) 的病理生理学中起核心作用。然而，Aβ 毒性的细胞机制仍知之甚少。在这里，我们表明 Aβ(25-35) 和 Aβ(1-40) 急性且差异地影响了小鼠中 3 类中隔 (MS) 神经元的特性。在谷氨酸能神经元中，Aβ 增加了放电频率并阻断了 A 电流 (I(A)) 和 M 电流 (I(M))。虽然 I(A) 阻断在其他 MS 神经元类型中相似，但 I(M) 的阻断是谷氨酸能神经元所特有的。I(M) 阻断和模拟 Aβ 阻断模拟了 Aβ 在谷氨酸能神经元中诱导的自发放电增加。钙成像显示，在对照条件下，谷氨酸能神经元很少放电，而非谷氨酸能神经元以 theta 频率同步放电。Aβ 增加了谷氨酸能神经元的放电率，而非谷氨酸能神经元失去了 theta 放电同步性。我们的结果表明，Aβ 通过降低 I(M) 诱导谷氨酸能神经元功能障碍，降低了 MS 的节律性，这可能会对海马体的节律生成产生负面影响，并导致阿尔茨海默病中观察到的记忆丧失。
