Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
Institute of Anatomy and Cell Biology, University of Heidelberg, Heidelberg, Germany.
PLoS One. 2019 Jan 15;14(1):e0209228. doi: 10.1371/journal.pone.0209228. eCollection 2019.
Several lines of evidence imply changes in inhibitory interneuron connectivity and subsequent alterations in oscillatory network activities in the pathogenesis of Alzheimer's Disease (AD). Recently, we provided evidence for an increased immunoreactivity of both the postsynaptic scaffold protein gephyrin and the GABAA receptor γ2-subunit in the hippocampus of young (1 and 3 months of age), APPPS1 mice. These mice represent a well-established model of cerebral amyloidosis, which is a hallmark of human AD. In this study, we demonstrate a robust increase of parvalbumin immunoreactivity and accentuated projections of parvalbumin positive (PV+) interneurons, which target perisomatic regions of pyramidal cells within the hippocampal subregions CA1 and CA3 of 3-month-old APPPS1 mice. Colocalisation studies confirmed a significant increase in the density of PV+ projections labeled with antibodies against a presynaptic (vesicular GABA transporter) and a postsynaptic marker (gephyrin) of inhibitory synapses within the pyramidal cell layer of CA1 and CA3. As perisomatic inhibition by PV+-interneurons is crucial for the generation of hippocampal network oscillations involved in spatial processing, learning and memory formation we investigated the impact of the putative enhanced perisomatic inhibition on two types of fast neuronal network oscillations in acute hippocampal slices: 1. spontaneously occurring sharp wave-ripple complexes (SPW-R), and 2. cholinergic γ-oscillations. Interestingly, both network patterns were generally preserved in APPPS1 mice similar to WT mice. However, the comparison of simultaneous CA3 and CA1 recordings revealed that the incidence and amplitude of SPW-Rs were significantly lower in CA1 vs CA3 in APPPS1 slices, whereas the power of γ-oscillations was significantly higher in CA3 vs CA1 in WT-slices indicating an impaired communication between the CA3 and CA1 network activities in APPPS1 mice. Taken together, our data demonstrate an increased GABAergic synaptic output of PV+ interneurons impinging on pyramidal cells of CA1 and CA3, which might limit the coordinated cross-talk between these two hippocampal areas in young APPPS1 mice and mediate long-term changes in synaptic inhibition during progression of amyloidosis.
有几条证据表明，在阿尔茨海默病（AD）的发病机制中，抑制性中间神经元的连接发生变化，随后振荡网络活动发生改变。最近，我们提供的证据表明，年轻（1 个月和 3 个月大）APPPS1 小鼠的海马中，突触后支架蛋白神经胶质蛋白和 GABA A 受体 γ2 亚基的免疫反应性增加。这些小鼠代表了一种成熟的脑淀粉样变性模型，这是人类 AD 的一个标志。在这项研究中，我们证明了 3 个月大的 APPPS1 小鼠海马 CA1 和 CA3 区中，PV+中间神经元的投射明显增强，而 PV+中间神经元的免疫反应性显著增加。共定位研究证实，在 CA1 和 CA3 的锥体细胞层中，用针对抑制性突触的突触前（囊泡 GABA 转运体）和突触后标志物（神经胶质蛋白）的抗体标记的 PV+投射的密度显著增加。由于 PV+中间神经元的树突抑制对于参与空间处理、学习和记忆形成的海马网络振荡的产生至关重要，我们研究了假定的增强的树突抑制对急性海马切片中两种快速神经元网络振荡的影响：1. 自发发生的尖波-涟漪复合物（SPW-R），2. 胆碱能γ-振荡。有趣的是，与 WT 小鼠相比，APPPS1 小鼠中的这两种网络模式通常都得到保留。然而，对 CA3 和 CA1 同时记录的比较表明，在 APPPS1 切片中，CA1 中的 SPW-R 的发生率和幅度明显低于 CA3，而 WT 切片中 CA3 中的γ-振荡的功率明显高于 CA1，表明 APPPS1 小鼠中 CA3 和 CA1 网络活动之间的通信受损。总之，我们的数据表明，PV+中间神经元的 GABA 能突触输出增加，影响 CA1 和 CA3 的锥体细胞，这可能限制了年轻 APPPS1 小鼠中这两个海马区之间的协调串扰，并介导淀粉样变性进展过程中突触抑制的长期变化。
