Northwestern University Interdepartmental PhD Program & Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Biostatistics Collaboration Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
J Physiol. 2020 May;598(10):1965-1985. doi: 10.1113/JP279561. Epub 2020 Apr 6.
The activity of local excitatory circuits of the subiculum has been suggested to be involved in the initiation of pathological activity in epileptic patients and experimental animal models of temporal lobe epilepsy. We have taken advantage of multimodal techniques to classify subicular cells in distinct subclasses and have investigated their morphofunctional properties and connectivity in vitro. Our results indicate that local subicular excitatory circuits are connected in a cell type-specific fashion and that synapses are preferentially established on basal vs. apical dendrites. We show that local excitatory circuits, isolated from extrasubicular inputs and pharmacologically disinhibited, are sufficient to initiate synchronous epileptiform activity in vitro. In conclusion, this work provides a high-resolution description of local excitatory circuits of the subiculum and highlights their mechanistic involvement in the generation of pathological activity.
The subiculum has been suggested to be involved in the initiation of pathological discharges in human patients and animal models of temporal lobe epilepsy. Although converging evidence has revealed the existence of functional diversity within its principal neurons, much less attention has been devoted to its intrinsic connectivity and whether its local excitatory circuits are sufficient to generate epileptiform activity. Here, we have directly addressed these two key points in mouse subicular slices. First, using multivariate techniques, we have distinguished two groups of principal cells, which we have termed type 1 and type 2. These subgroups roughly overlap with what were classically indicated as regular and bursting cells, and showed differences in the extension and complexity of their apical dendrites. Functional connectivity was found both between similar (homotypic) and different (heterotypic) types of cells, with a marked asymmetry within heterotypic pairs. Unitary excitatory postsynaptic potentials (uEPSPs) revealed a high degree of variability both in amplitude, failure rate, rise time and half-width. Post hoc analysis of functionally connected pairs suggested that the observed uEPSPs were mediated by few contact sites, predominantly located on the basal dendrites. When surgically isolated from extrasubicular excitatory afferents, pharmacologically disinhibited subicular slices generated hyper-synchronous discharges. Thus, we conclude that local subicular excitatory circuits, connected according to cell type-specific rules, are sufficient to promote epileptiform activity. This conclusion fits well with a previous suggestion that local subicular events, purely mediated by excitatory connections, may underlie the pre-ictal discharges that govern interictal-ictal transitions.
已有研究表明，海马下托局部兴奋性回路的活动可能参与了癫痫患者和颞叶癫痫实验动物模型中病理性活动的起始。我们利用多模态技术对海马下托细胞进行分类，研究了其在体外的形态功能特性和连接方式。结果表明，局部海马下托兴奋性回路以细胞类型特异性的方式连接，并且突触优先建立在基底突而非树突上。我们还发现，从细胞外传入中分离并经药理学去抑制的局部兴奋性回路足以在体外引发同步癫痫样活动。总之，本工作提供了海马下托局部兴奋性回路的高分辨率描述，并强调了其在病理性活动产生中的机械性参与。
已有研究表明，海马下托可能参与了人类患者和颞叶癫痫动物模型中病理性放电的起始。尽管越来越多的证据表明其主要神经元存在功能多样性，但对其内在连接以及其局部兴奋性回路是否足以产生癫痫样活动的关注较少。本研究直接解决了这两个在小鼠海马下托切片中的关键问题。首先，我们使用多元技术区分了两类主要细胞，我们将其称为 1 型和 2 型。这两个亚组大致与经典上的规则细胞和爆发细胞重叠，并在其树突的延伸和复杂度上表现出差异。在相似（同型）和不同（异型）类型的细胞之间发现了功能连接，异型对之间存在明显的不对称性。单位兴奋性突触后电位（uEPSP）在幅度、失败率、上升时间和半宽度上都表现出高度的可变性。对功能连接对的事后分析表明，观察到的 uEPSP 是由少数接触点介导的，主要位于基底突上。当从细胞外兴奋性传入中分离并经药理学去抑制后，海马下托切片会产生超同步放电。因此，我们得出结论，根据细胞类型特异性规则连接的局部海马下托兴奋性回路足以促进癫痫样活动。这一结论与先前的一个观点相符，即局部海马下托事件纯粹由兴奋性连接介导，可能是导致控制发作间期-发作转换的发作前期放电的基础。
