Center for Dementia Research, the Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
Center for Dementia Research, the Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA; Department of Child & Adolescent Psychiatry, Neuroscience & Physiology, and Psychiatry, New York University Langone Health, New York, NY 10016, USA; Neuroscience Institute, New York University Langone Health, New York, NY 10016, USA.
Neurobiol Dis. 2021 May;152:105274. doi: 10.1016/j.nbd.2021.105274. Epub 2021 Jan 20.
It has been reported that hyperexcitability occurs in a subset of patients with Alzheimer's disease (AD) and hyperexcitability could contribute to the disease. Several studies have suggested that the hippocampal dentate gyrus (DG) may be an important area where hyperexcitability occurs. Therefore, we tested the hypothesis that the principal DG cell type, granule cells (GCs), would exhibit changes at the single-cell level which would be consistent with hyperexcitability and might help explain it. We used the Tg2576 mouse, where it has been shown that hyperexcitability is robust at 2-3 months of age. GCs from 2 to 3-month-old Tg2576 mice were compared to age-matched wild type (WT) mice. Effects of muscarinic cholinergic antagonism were tested because previously we found that Tg2576 mice exhibited hyperexcitability in vivo that was reduced by the muscarinic cholinergic antagonist atropine, counter to the dogma that in AD one needs to boost cholinergic function. The results showed that GCs from Tg2576 mice exhibited increased frequency of spontaneous excitatory postsynaptic potentials/currents (sEPSP/Cs) and reduced frequency of spontaneous inhibitory synaptic events (sIPSCs) relative to WT, increasing the excitation:inhibition (E:I) ratio. There was an inward NMDA receptor-dependent current that we defined here as a novel synaptic current (nsC) in Tg2576 mice because it was very weak in WT mice. Intrinsic properties were distinct in Tg2576 GCs relative to WT. In summary, GCs of the Tg2576 mouse exhibit early electrophysiological alterations that are consistent with increased synaptic excitation, reduced inhibition, and muscarinic cholinergic dysregulation. The data support previous suggestions that the DG contributes to hyperexcitability and there is cholinergic dysfunction early in life in AD mouse models.
据报道，阿尔茨海默病（AD）患者中有一部分存在过度兴奋，而过度兴奋可能会导致疾病的发生。多项研究表明，海马齿状回（DG）可能是过度兴奋发生的一个重要区域。因此，我们测试了以下假说，即 DG 的主要细胞类型——颗粒细胞（GCs）在单细胞水平上会发生变化，这些变化与过度兴奋一致，并可能有助于解释过度兴奋的原因。我们使用了 Tg2576 小鼠，该模型已被证明在 2-3 月龄时表现出明显的过度兴奋。将 2-3 月龄的 Tg2576 小鼠的 GCs 与年龄匹配的野生型（WT）小鼠进行比较。我们测试了毒蕈碱型乙酰胆碱能受体拮抗剂的作用，因为之前我们发现 Tg2576 小鼠体内存在过度兴奋，而毒蕈碱型乙酰胆碱能受体拮抗剂阿托品可以降低这种过度兴奋，这与 AD 患者需要增强胆碱能功能的观点相悖。结果表明，与 WT 相比，Tg2576 小鼠的 GCs 表现出更高的自发性兴奋性突触后电位/电流（sEPSP/Cs）频率和更低的自发性抑制性突触事件（sIPSCs）频率，从而增加了兴奋：抑制（E:I）比值。我们在这里定义了一种新的突触电流（nsC），因为在 WT 小鼠中这种电流非常弱。与 WT 相比，Tg2576 小鼠的 GCs 具有明显不同的内在特性。综上所述，Tg2576 小鼠的 GCs 表现出早期的电生理改变，这些改变与突触兴奋增加、抑制减少以及毒蕈碱型乙酰胆碱能功能失调相一致。这些数据支持了之前的观点，即 DG 有助于过度兴奋，并且在 AD 小鼠模型中，生命早期就存在胆碱能功能障碍。
