Mackenzie-Gray Scott Connie A, Pelkey Kenneth A, Caccavano Adam P, Abebe Daniel, Lai Mandy, Black Khayla N, Brown Nicolette D, Trevelyan Andrew J, McBain Chris J
Section on Cellular and Synaptic Physiology, NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, United States.
Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Front Synaptic Neurosci. 2022 May 11;14:857608. doi: 10.3389/fnsyn.2022.857608. eCollection 2022.
Recent studies have implicated impaired Parvalbumin Fast-Spiking Interneuron (PVIN) function as a precipitating factor underlying abnormalities in network synchrony, oscillatory rhythms, and cognition associated with Alzheimer's disease (AD). However, a complete developmental investigation of potential gamma deficits, induced by commonly used carbachol or kainate in slice preparations, within AD model mice is lacking. We examined gamma oscillations using field recordings in acute hippocampal slices from and control mice, through the period of developing pathology, starting at 3 months of age, when there is minimal plaque presence in the hippocampus, through to 12+ months of age, when plaque burden is high. In addition, we examined PVIN participation in gamma rhythms using targeted cell-attached recordings of genetically-reported PVINs, in both wild type and mutant mice. In parallel, a developmental immunohistochemical characterisation probing the PVIN-associated expression of PV and perineuronal nets (PNNs) was compared between control and mice. Remarkably, this comprehensive longitudinal evaluation failed to reveal any obvious correlations between PVIN deficits (electrical and molecular), circuit rhythmogenesis (gamma frequency and power), and Aβ deposits/plaque formation. By 6-12 months, animals have extensive plaque formation throughout the hippocampus. However, a deficit in gamma oscillatory power was only evident in the oldest animals (12+ months), and only when using kainate, and not carbachol, to induce the oscillations. We found no difference in PV firing or phase preference during kainate-induced oscillations in younger or older mice compared to control, and a reduction of PV and PNNs only in the oldest mice. The lack of a clear relationship between PVIN function, network rhythmicity, and plaque formation in our study highlights an unexpected resilience in PVIN function in the face of extensive plaque pathology associated with this model, calling into question the presumptive link between PVIN pathology and Alzheimer's progression.
最近的研究表明，小白蛋白快速放电中间神经元（PVIN）功能受损是与阿尔茨海默病（AD）相关的网络同步性、振荡节律和认知异常的一个促成因素。然而，在AD模型小鼠中，缺乏对常用的卡巴胆碱或海藻酸在脑片制备中诱导的潜在γ波缺陷的完整发育研究。我们使用急性海马脑片的场记录，从3个月大（此时海马中斑块极少）到12个月以上（此时斑块负担很高）的疾病发展阶段，对AD小鼠和对照小鼠的γ振荡进行了检测。此外，我们在野生型和突变型小鼠中，使用基因报告的PVIN的靶向细胞贴附记录，研究了PVIN对γ节律的参与情况。同时，对对照小鼠和AD小鼠之间PV和神经元周围网络（PNN）的与PVIN相关的表达进行了发育性免疫组织化学表征比较。值得注意的是，这项全面的纵向评估未能揭示PVIN缺陷（电生理和分子方面）、电路节律发生（γ频率和功率）与Aβ沉积/斑块形成之间的任何明显相关性。到6至12个月时，AD动物在整个海马中形成了广泛的斑块。然而，γ振荡功率的缺陷仅在最老的AD动物（12个月以上）中明显，且仅在使用海藻酸而非卡巴胆碱诱导振荡时出现。我们发现，与对照相比，在年轻或年老的AD小鼠中海藻酸诱导振荡期间，PV放电或相位偏好没有差异，并且仅在最老的AD小鼠中PV和PNN减少。我们的研究中PVIN功能、网络节律性和斑块形成之间缺乏明确关系，凸显了在面对与该模型相关的广泛斑块病理时，PVIN功能具有意想不到的弹性，这让人质疑PVIN病理与阿尔茨海默病进展之间的假定联系。
