Neuronal Oscillations Laboratory, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, 17164, Solna, Sweden.
Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, 14183, Huddinge, Sweden.
Transl Psychiatry. 2021 Apr 9;11(1):212. doi: 10.1038/s41398-021-01332-8.
Gamma and theta brain rhythms play important roles in cognition and their interaction can affect gamma oscillation features. Hippocampal theta oscillations depend on cholinergic and GABAergic input from the medial septum-diagonal band of Broca. These projecting neurons undergo degeneration during aging and maintain high levels of neurotrophin receptor p75 (p75). p75 mediates both apoptosis and survival and its expression is increased in Alzheimer's disease (AD) patients. Here, we investigate the importance of p75 for the cholinergic input to the hippocampus. Performing extracellular recordings in brain slices from p75 knockout mice (p75) in presence of the muscarinic agonist carbachol, we find that gamma oscillation power and rhythmicity are increased compared to wild-type (WT) mice. Furthermore, gamma activity is more phase-locked to the underlying theta rhythm, which renders a stronger coupling of both rhythms. On the cellular level, we find that fast-spiking interneurons (FSNs) fire more synchronized to a preferred gamma phase in p75 mice. The excitatory input onto FSN is more rhythmic displaying a higher similarity with the concomitant gamma rhythm. Notably, the ablation of p75 counteracts the Aβ-induced degradation of gamma oscillations and its nesting within the underlying theta rhythm. Our results show that the lack of p75 signaling could promote stronger cholinergic modulation of the hippocampal gamma rhythm, suggesting an involvement of p75 in the downregulation of cognition-relevant hippocampal network dynamics in pathologies. Moreover, functional data provided here suggest p75 as a suitable target in the search for efficacious treatments to counteract the loss of cognitive function observed in amyloid-driven pathologies such as AD.
伽马和θ脑电波在认知中起着重要作用，它们的相互作用可以影响伽马振荡的特征。海马θ振荡依赖于来自内侧隔核-布鲁卡斜角带的胆碱能和 GABA 能输入。这些投射神经元在衰老过程中会发生退化，并保持高水平的神经营养因子受体 p75（p75）。p75 介导细胞凋亡和存活，其表达在阿尔茨海默病（AD）患者中增加。在这里，我们研究了 p75 对海马胆碱能输入的重要性。在存在毒蕈碱激动剂 carbachol 的情况下，在 p75 敲除小鼠（p75）的脑切片中进行细胞外记录，我们发现与野生型（WT）小鼠相比，γ 振荡的功率和节律性增加。此外，γ 活动与基础 θ 节律的相位锁定更强，从而使两种节律的耦合更强。在细胞水平上，我们发现快速放电中间神经元（FSNs）在 p75 小鼠中更同步地发射到首选的 γ 相位。FSN 上的兴奋性输入更有节奏，与伴随的 γ 节律具有更高的相似性。值得注意的是，p75 的消融可抵消 Aβ 诱导的 γ 振荡的降解及其嵌套在基础 θ 节律内。我们的研究结果表明，缺乏 p75 信号可能会促进海马 γ 节律更强的胆碱能调制，这表明 p75 参与了认知相关海马网络动力学在病理中的下调。此外，这里提供的功能数据表明 p75 是寻找有效治疗方法以对抗淀粉样蛋白驱动的病理如 AD 中观察到的认知功能丧失的合适靶点。
