Myasthenia Gravis: From the Viewpoint of Pathogenicity Focusing on Acetylcholine Receptor Clustering, Trans-Synaptic Homeostasis and Synaptic Stability.
- 作者列表："Takamori M
:Myasthenia gravis (MG) is a disease of the postsynaptic neuromuscular junction (NMJ) where nicotinic acetylcholine (ACh) receptors (AChRs) are targeted by autoantibodies. Search for other pathogenic antigens has detected the antibodies against muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein-related protein 4 (Lrp4), both causing pre- and post-synaptic impairments. Agrin is also suspected as a fourth pathogen. In a complex NMJ organization centering on MuSK: (1) the Wnt non-canonical pathway through the Wnt-Lrp4-MuSK cysteine-rich domain (CRD)-Dishevelled (Dvl, scaffold protein) signaling acts to form AChR prepatterning with axonal guidance; (2) the neural agrin-Lrp4-MuSK (Ig1/2 domains) signaling acts to form rapsyn-anchored AChR clusters at the innervated stage of muscle; (3) adaptor protein Dok-7 acts on MuSK activation for AChR clustering from "inside" and also on cytoskeleton to stabilize AChR clusters by the downstream effector Sorbs1/2; (4) the trans-synaptic retrograde signaling contributes to the presynaptic organization via: (i) Wnt-MuSK CRD-Dvl-β catenin-Slit 2 pathway; (ii) Lrp4; and (iii) laminins. The presynaptic Ca2+ homeostasis conditioning ACh release is modified by autoreceptors such as M1-type muscarinic AChR and A2A adenosine receptors. The post-synaptic structure is stabilized by: (i) laminin-network including the muscle-derived agrin; (ii) the extracellular matrix proteins (including collagen Q/perlecan and biglycan which link to MuSK Ig1 domain and CRD); and (iii) the dystrophin-associated glycoprotein complex. The study on MuSK ectodomains (Ig1/2 domains and CRD) recognized by antibodies suggested that the MuSK antibodies were pathologically heterogeneous due to their binding to multiple functional domains. Focussing one of the matrix proteins, biglycan which functions in the manner similar to collagen Q, our antibody assay showed the negative result in MG patients. However, the synaptic stability may be impaired by antibodies against MuSK ectodomains because of the linkage of biglycan with MuSK Ig1 domain and CRD. The pathogenic diversity of MG is discussed based on NMJ signaling molecules.
: 重症肌无力 (MG) 是突触后神经肌肉接头 (NMJ) 的一种疾病，烟碱乙酰胆碱 (ACh) 受体 (AChRs) 被自身抗体靶向。搜索其他致病抗原已检测到抗肌肉特异性酪氨酸激酶 (MuSK) 和低密度脂蛋白相关蛋白 4 (Lrp4) 的抗体,两者都引起突触前和突触后损伤。Agrin 也被怀疑是第四种病原体。在一个以麝香为中心的复杂 NMJ 组织中: (1) Wnt 非经典途径通过 Wnt-Lrp4-MuSK 富含半胱氨酸的结构域 (CRD) 蓬乱 (Dvl，支架蛋白) 信号传导作用与轴突引导形成 AChR 前模式; (2) 神经 agrin-Lrp4-MuSK (Ig1/2 结构域)信号作用在肌肉的神经支配阶段形成 rapsyn 锚定的 AChR 簇; (3) 接头蛋白 Dok-7 从 “内部” 作用于 MuSK 激活 AChR 聚集，也作用于细胞骨架，通过下游效应器 Sorbs1/2 稳定 AChR 聚集; (4) 跨突触逆行信号通过以下途径促进突触前组织:(I) Wnt-MuSK CRD-Dvl-β catenin-Slit 2 通路; (ii) Lrp4; 和 (iii) 层粘连蛋白。突触前 Ca2 + 稳态调理 ACh 释放被自感受器如 M1-type 毒蕈碱 AChR 和 A2A 腺苷受体修饰。突触后结构通过以下方式稳定 :( i) 层粘连蛋白网络，包括肌肉来源的 agrin; (ii) 细胞外基质蛋白 (包括与 MuSK Ig1 结构域和 CRD 相关的胶原 Q/perlecan 和 biglycan); 和 (iii) dystrophin 相关糖蛋白复合物。对抗体识别的麝香外域 (Ig1/2 结构域和 CRD) 的研究表明，麝香抗体由于与多个功能结构域结合而具有病理异质性。聚焦其中一个基质蛋白，biglycan，其功能类似于胶原 Q，我们的抗体检测显示 MG 患者的阴性结果。然而，由于 biglycan 与 MuSK Ig1 结构域和 CRD 的连接，针对 MuSK 胞外域的抗体可能会损害突触稳定性。基于 NMJ 信号分子讨论了 MG 的致病性多样性。
METHODS::In recent years, transcranial electrical stimulation (tES) has been used to improve cognitive and perceptual abilities and to boost learning. In the visual domain, transcranial random noise stimulation (tRNS), a type of tES in which electric current is randomly alternating in between two electrodes at high frequency, has shown potential in inducing long lasting perceptual improvements when coupled with tasks such as contrast detection. However, its cortical mechanisms and online effects have not been fully understood yet, and it is still unclear whether these long-term improvements are due to early-stage perceptual enhancements of contrast sensitivity or later stage mechanisms such as learning consolidation. Here we tested tRNS effects on multiple spatial frequencies and orientation, showing that tRNS enhances detection of a low contrast Gabor, but only for oblique orientation and high spatial frequency (12 cycles per degree of visual angle). No improvement was observed for low contrast and vertical stimuli. These results indicate that tRNS can enhance contrast sensitivity already after one training session, however this early onset is dependent on characteristics of the stimulus such as spatial frequency and orientation. In particular, the shallow depth of tRNS is likely to affect superficial layers of the visual cortex where neurons have higher preferred spatial frequencies than cells in further layers, while the lack of effect on vertical stimuli might reflect the optimization of the visual system to see cardinally oriented low contrast stimuli, leaving little room for short-term improvement. Taken together, these results suggest that online tRNS effects on visual perception are the result of a complex interaction between stimulus intensity and cortical anatomy, consistent with previous literature on brain stimulation.
METHODS:OBJECTIVE:There is growing interest in treating diseases by electrical stimulation and block of peripheral autonomic nerves, but a paucity of studies on excitation and block of small diameter autonomic axons. We conducted in vivo quantification of the strength-duration properties, activity-dependent slowing (ADS), and responses to kilohertz frequency (KHF) signals for the rat vagus nerve (VN). APPROACH:We conducted acute in vivo experiments in urethane-anesthetised rats. We placed two cuff electrodes on the left cervical VN and one cuff electrode on the anterior subdiaphragmatic VN. The rostral cervical cuff was used to deliver pulses to quantify recruitment and ADS. The caudal cervical cuff was used to deliver KHF signals. The subdiaphragmatic cuff was used to record compound action potentials (CAPs). MAIN RESULTS:We quantified the input-output recruitment and strength-duration curves. Fits to the data using standard strength-duration equations were qualitatively similar, but the resulting chronaxie and rheobase estimates varied substantially. We measured larger thresholds for the slowest fibres (0.5 to 1 m/s), especially at shorter pulse widths. Using a novel cross-correlation CAP-based analysis, we measured ADS of ~2.3% after 3 min of 2 Hz stimulation, which is comparable to ADS reported for sympathetic efferents in somatic nerves, but much smaller than ADS in cutaneous nociceptors. We found greater ADS with higher stimulation frequency and non-monotonic changes in CV in select cases. We found monotonically increasing block thresholds across frequencies from 10 to 80 kHz for both fast and slow fibres. Further, following 25 s of KHF signal, neural conduction could require tens of seconds to recover. SIGNIFICANCE:The quantification of mammalian autonomic nerve responses to conventional and KHF signals provides essential information for development of peripheral nerve stimulation therapies and for understanding their mechanisms of action.
METHODS:BACKGROUND:Early accounts of forced thought were reported at the onset of a focal seizure, and characterized as vague, repetitive, and involuntary intellectual auras distinct from perceptual or psychic hallucinations or illusions. Here, we examine the neural underpinnings involved in conceptual thought by presenting a series of 3 patients with epilepsy reporting intrusive thoughts during electrical stimulation of the left lateral prefrontal cortex (PFC) during invasive surgical evaluation. We illustrate the widespread networks involved through two independent brain imaging modalities: resting state functional magnetic resonance imaging (fMRI) (rs-fMRI) and task-based meta-analytic connectivity modeling (MACM). METHODS:We report the clinical and stimulation characteristics of three patients with left hemispheric language dominance who demonstrate forced thought with functional mapping. To examine the brain networks underlying this phenomenon, we used the regions of interest (ROI) centered at the active electrode pairs. We modeled functional networks using two approaches: (1) rs-fMRI functional connectivity analysis, representing 81 healthy controls and (2) meta-analytic connectivity modeling (MACM), representing 8260 healthy subjects. We also determined the overlapping regions between these three subjects' rs-fMRI and MACM networks through a conjunction analysis. RESULTS:We identified that left PFC was associated with a large-scale functional network including frontal, temporal, and parietal regions, a network that has been associated with multiple cognitive functions including semantics, speech, attention, working memory, and explicit memory. CONCLUSIONS:We illustrate the neural networks involved in conceptual thought through a unique patient population and argue that PFC supports this function through activation of a widespread network.