GABAergic interneuron

  • 文章类型: Journal Article
    轴突细胞(AACs),也被称为大脑皮层中的枝形吊灯细胞(ChCs),是新皮层中描述的最独特的GABA能中间神经元类型,海马体,和基底外侧杏仁核(BLA)。AAC在其轴突初始部分(AIS)选择性神经支配谷氨酸能投射神经元(PNs),因此,可以对PN尖峰施加决定性控制并调节PN功能集合。然而,整个大脑的分布,突触连接,AAC的电路功能仍然知之甚少,主要是由于缺乏具体可靠的实验工具。这里,我们建立了一种交叉遗传策略,根据其谱系(Nkx2.1)和分子(Unc5b,Pthlh)标记。我们发现AAC基本上部署在所有的大脑皮层来源的大脑结构中,不仅包括背侧大脑皮层衍生的新皮质和内侧大脑皮层衍生的海马结构,但也有来自横向的皮层-岛叶复合物,和腹侧大脑皮层衍生的扩展杏仁核复合体和嗅觉中心。嗅前核中也有大量的AAC,taeniatecta,和侧隔。AAC在新皮质区域和层以及海马结构的各个子区域中显示出密度的特征性变化。新皮质AAC包含多个层状亚型,具有不同的树突状和轴突树状模式。来自AACs的逆行单突触追踪穿过新皮质,海马,和BLA区域揭示了突触输入的共享和不同模式。AAC的具体和全面的靶向有助于研究它们的发育遗传程序和跨大脑结构的回路功能。为理解跨大脑区域和物种的真实细胞类型的保护和变化提供了一个基本事实平台。
    无论我们是在记忆事实,还是在对一声巨响做出反应,不同大脑区域的神经细胞必须能够通过精确的,有意义的信号。称为中间神经元的特殊神经细胞充当“交通信号灯”,以精确调节这些信息在神经回路中的流动时间和位置。轴突细胞是一种罕见的抑制性中间神经元,被认为对于控制不同组兴奋性神经元之间的信息传递特别重要。这是因为它们只连接到靶细胞的一个关键部分——轴突初始部分——在那里启动了大脑交流所需的电信号(称为动作电位)。由于轴突细胞是抑制性中间神经元,这种联系有效地允许他们“否决”这些信号的产生。尽管已经使用传统的解剖学方法在三个大脑区域中鉴定了轴-轴突细胞,没有现成的“标签”可以可靠地识别它们。因此,关于这些细胞的许多信息仍然未知,包括它们在哺乳动物大脑中的分布。为了解决这个问题,Raudales等人。研究了哪些基因在轴突细胞中打开,而不是在其他细胞中打开,确定一个独特的分子特征,可以用来标记,记录,操纵这些细胞。对小鼠脑组织的显微镜成像显示,轴突细胞已经被鉴定出来,它们存在于比以前认为的更多的大脑区域,包括大脑皮层的几乎所有区域,甚至下丘脑,控制着许多与生俱来的行为。轴突细胞也有不同的“连接”,取决于它们的位置;例如,与记忆和情绪相关的大脑区域比其他区域有更广泛的输入联系。Raudales等人的发现。提供,第一次,一种直接追踪和操纵大脑轴突细胞的方法。由于轴突细胞的功能障碍也与癫痫和精神分裂症等神经系统疾病有关,深入了解它们的分布和连通性可能有助于开发针对这些疾病的更好治疗方法。
    Axo-axonic cells (AACs), also called chandelier cells (ChCs) in the cerebral cortex, are the most distinctive type of GABAergic interneurons described in the neocortex, hippocampus, and basolateral amygdala (BLA). AACs selectively innervate glutamatergic projection neurons (PNs) at their axon initial segment (AIS), thus may exert decisive control over PN spiking and regulate PN functional ensembles. However, the brain-wide distribution, synaptic connectivity, and circuit function of AACs remain poorly understood, largely due to the lack of specific and reliable experimental tools. Here, we have established an intersectional genetic strategy that achieves specific and comprehensive targeting of AACs throughout the mouse brain based on their lineage (Nkx2.1) and molecular (Unc5b, Pthlh) markers. We discovered that AACs are deployed across essentially all the pallium-derived brain structures, including not only the dorsal pallium-derived neocortex and medial pallium-derived hippocampal formation, but also the lateral pallium-derived claustrum-insular complex, and the ventral pallium-derived extended amygdaloid complex and olfactory centers. AACs are also abundant in anterior olfactory nucleus, taenia tecta, and lateral septum. AACs show characteristic variations in density across neocortical areas and layers and across subregions of the hippocampal formation. Neocortical AACs comprise multiple laminar subtypes with distinct dendritic and axonal arborization patterns. Retrograde monosynaptic tracing from AACs across neocortical, hippocampal, and BLA regions reveal shared as well as distinct patterns of synaptic input. Specific and comprehensive targeting of AACs facilitates the study of their developmental genetic program and circuit function across brain structures, providing a ground truth platform for understanding the conservation and variation of a bona fide cell type across brain regions and species.
    Whether we are memorising facts or reacting to a loud noise, nerve cells in different brain areas must be able to communicate with one another through precise, meaningful signals. Specialized nerve cells known as interneurons act as “traffic lights” to precisely regulate when and where this information flows in neural circuits. Axo-axonic cells are a rare type of inhibitory interneuron that are thought to be particularly important for controlling the passage of information between different groups of excitatory neurons. This is because they only connect to one key part of their target cell – the axon-initial segment – where the electrical signals needed for brain communication (known as action potentials) are initiated. Since axo-axonic cells are inhibitory interneurons, this connection effectively allows them to ‘veto’ the generation of these signals at their source. Although axo-axonic cells have been identified in three brain regions using traditional anatomical methods, there were no ‘tags’ readily available that can reliably identify them. Therefore, much about these cells remained unknown, including how widespread they are in the mammalian brain. To solve this problem, Raudales et al. investigated which genes are switched on in axo-axonic cells but not in other cells, identifying a unique molecular signature that could be used to mark, record, and manipulate these cells. Microscopy imaging of brain tissue from mice in which axo-axonic cells had been identified revealed that they are present in many more brain areas than previously thought, including nearly all regions of the broadly defined cerebral cortex and even the hypothalamus, which controls many innate behaviors. Axo-axonic cells were also ‘wired up’ differently, depending on where they were located; for example, those in brain areas associated with memory and emotions had wider-ranging input connections than other areas. The finding of Raudales et al. provide, for the first time, a method to directly track and manipulate axo-axonic cells in the brain. Since dysfunction in axo-axonic cells is also associated with neurological disorders like epilepsy and schizophrenia, gaining an insight into their distribution and connectivity could help to develop better treatments for these conditions.
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  • 文章类型: Journal Article
    不同神经元类型的突触连接模式和生理特性由不同的基因集形成。我们的研究表明,在老鼠的前脑,抑制性GABA能中间神经元的转录谱受Nr4a1调节,Nr4a1是一种孤儿核受体,其表达是由感觉经验短暂诱导的,是正常学习所必需的。Nr4a1对小白蛋白和生长抑素阳性中间神经元的局部轴突布线产生对比作用,神经支配其突触后伴侣的不同亚细胞结构域。这些中间神经元中Nr4a1活性的丧失导致双向,跨多个基因家族的细胞类型特异性转录转换,包括那些涉及表面粘附和排斥。我们的发现表明,组合突触组织代码具有惊人的灵活性,并突出了诱导型转录因子可以影响神经回路结构和功能的机制。
    The patterns of synaptic connectivity and physiological properties of diverse neuron types are shaped by distinct gene sets. Our study demonstrates that, in the mouse forebrain, the transcriptional profiles of inhibitory GABAergic interneurons are regulated by Nr4a1, an orphan nuclear receptor whose expression is transiently induced by sensory experiences and is required for normal learning. Nr4a1 exerts contrasting effects on the local axonal wiring of parvalbumin- and somatostatin-positive interneurons, which innervate different subcellular domains of their postsynaptic partners. The loss of Nr4a1 activity in these interneurons results in bidirectional, cell-type-specific transcriptional switches across multiple gene families, including those involved in surface adhesion and repulsion. Our findings reveal that combinatorial synaptic organizing codes are surprisingly flexible and highlight a mechanism by which inducible transcription factors can influence neural circuit structure and function.
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  • 文章类型: Journal Article
    纯合子布朗克斯·华策(BV)小鼠,这表明听力受损,还表现出焦虑,伴有皮质小清蛋白(PV)阳性GABA能中间神经元的减少。最近,在bv小鼠中发现了剪接因子Ser/Arg重复矩阵4(Srrm4)的突变。然而,Srrm4突变对焦虑的细胞影响尚不清楚.这里,我们检验了我们的假设,即bv突变体主要通过细胞内在病理影响中间神经元,导致中间神经元减少,从而引起焦虑。我们发现,在bv/bv小鼠中,焦虑在6周龄时变得明显。然而,原位杂交显示Srrm4在中间神经元中不表达,而是在锥体神经元中占主导地位。此外,当焦虑变得明显时,bv/bv皮层中PV阳性GABA能中间神经元的数量没有减少。然而,同时存在来自中间神经元的GABA能传递的电生理异常。GABAA受体的药理学阻断显示bv/bv小鼠的兴奋性增加,尽管Srrm4下游基因的表达没有发生重大变化,Kcc2,调节GABA能传递时的氯化物通量。这些发现表明,bv相关的Srrm4突变主要涉及中枢神经系统的突触后GABA能传递,这可能与bv/bv小鼠的焦虑表型有关。
    The homozygous Bronx waltzer (bv) mouse, which shows hearing impairment, also exhibits anxiety accompanied by a reduction in cortical parvalbumin (PV)-positive GABAergic interneurons. Recently, a mutation in splicing factor Ser/Arg repetitive matrix 4 (Srrm4) was found in bv mice. However, the cellular consequences of the Srrm4 mutation for anxiety remain unknown. Here, we tested our hypothesis that bv mutant primarily affects interneurons through a cell-intrinsic pathology that leads to a reduction of interneurons and consequently causes anxiety. We found that the anxiety becomes apparent at 6 weeks of age in bv/bv mice. However, in situ hybridization revealed that Srrm4 is not expressed in interneurons, but rather dominates in pyramidal neurons. In addition, the PV-positive GABAergic interneurons were not reduced in number in the bv/bv cortex when anxiety became evident. However, electrophysiological abnormality of GABAergic transmission from interneurons was concomitantly present. Pharmacological blockage of GABAA receptors revealed increased excitability in bv/bv mice, although no gross change occurred in the expression of an Srrm4-downstream gene, Kcc2, which regulates chloride flux upon GABAergic transmission. These findings suggest that the bv-associated Srrm4 mutation mainly involves post-synaptic GABAergic transmission in the central nervous system, which may be associated with the anxiety phenotype in bv/bv mice.
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  • 文章类型: Journal Article
    NADH脱氢酶(泛醌还原酶)铁硫蛋白4(NDUFS4)基因突变,编码OXFOS复合物I(CI)的关键结构亚基,导致儿童中最常见的线粒体疾病形式,称为Leigh综合征(LS)。和其他线粒体疾病一样,癫痫发作是LS最重要的临床特征之一。这些癫痫发作通常很难治疗,并且是疾病预后不良的迹象。具有全身Ndufs4KO的小鼠是经过充分验证的LS模型;它们表现出癫痫和LS的一些其他临床特征。我们先前已经表明,仅在GABA能中间神经元(Gad2-Ndufs4-KO)中具有Ndufs4KO的小鼠再现了在全球KO小鼠中观察到的严重癫痫表型。该观察表明,这些小鼠代表了从该疾病的其他临床表现中分离的优异的LS癫痫模型。为了进一步表征这种癫痫表型,我们调查了Gad2-Ndufs4-KO小鼠对某些外源性癫痫发作触发因素的癫痫发作易感性.然后,使用电生理学,成像,和免疫组织化学,我们研究了细胞,生理,Ndufs4KO在GABA能中间神经元中的神经解剖学后果。GABA能中间神经元中Ndufs4的纯合KO导致对外源性癫痫发作触发的突出易感性,受损的中间神经元兴奋性和中间神经元丢失。最后,我们发现海马和皮质参与了Gad2-Ndufs4-KO小鼠癫痫发作活动的产生。这些发现进一步定义了LS癫痫表型,并为LS和其他线粒体疾病中癫痫的细胞机制提供了重要见解。
    Mutations in the NADH dehydrogenase (ubiquinone reductase) iron‑sulfur protein 4 (NDUFS4) gene, which encodes for a key structural subunit of the OXFOS complex I (CI), lead to the most common form of mitochondrial disease in children known as Leigh syndrome (LS). As in other mitochondrial diseases, epileptic seizures constitute one of the most significant clinical features of LS. These seizures are often very difficult to treat and are a sign of poor disease prognosis. Mice with whole-body Ndufs4 KO are a well-validated model of LS; they exhibit epilepsy and several other clinical features of LS. We have previously shown that mice with Ndufs4 KO in only GABAergic interneurons (Gad2-Ndufs4-KO) reproduce the severe epilepsy phenotype observed in the global KO mice. This observation indicated that these mice represent an excellent model of LS epilepsy isolated from other clinical manifestations of the disease. To further characterize this epilepsy phenotype, we investigated seizure susceptibility to selected exogenous seizure triggers in Gad2-Ndufs4-KO mice. Then, using electrophysiology, imaging, and immunohistochemistry, we studied the cellular, physiological, and neuroanatomical consequences of Ndufs4 KO in GABAergic interneurons. Homozygous KO of Ndufs4 in GABAergic interneurons leads to a prominent susceptibility to exogenous seizure triggers, impaired interneuron excitability and interneuron loss. Finally, we found that the hippocampus and cortex participate in the generation of seizure activity in Gad2-Ndufs4-KO mice. These findings further define the LS epilepsy phenotype and provide important insights into the cellular mechanisms underlying epilepsy in LS and other mitochondrial diseases.
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  • 文章类型: Journal Article
    背景:脑脊液和血液中Thr181磷酸化的tau蛋白(p-tau181)是阿尔茨海默病(AD)的敏感生物标志物。p-tau181水平的升高与淀粉样蛋白-β(Aβ)病理和AD早期神经原纤维缠结形成密切相关;然而,p-tau181与Aβ介导的病理学之间的关系尚不清楚。我们最近报道,p-tau181代表具有Aβ病理(AppNLGF)的小鼠的轴突异常。然而,这些p-tau181阳性轴突的神经元亚型起源仍然难以捉摸。
    目的:本研究的主要目的是通过对AppNLGF小鼠大脑的免疫组织化学分析来区分神经元亚型并阐明与p-tau181阳性轴突相关的损伤。
    方法:p-tau181与(1)囊泡乙酰胆碱转运体或去甲肾上腺素转运体阳性的无髓鞘轴突和(2)囊泡谷氨酸转运体阳性的有髓鞘轴突之间的定位,囊泡GABA转运蛋白,分析了24个月大的AppNLGF和没有Aβ病理的对照小鼠的大脑中的或小白蛋白。还比较了这些轴突的密度。
    结果:胆碱能或去甲肾上腺素能神经元的无髓鞘轴突与p-tau181不重叠。相比之下,p-tau181信号与小白蛋白阳性GABA能中间神经元的有髓轴突共定位,但与谷氨酸能神经元无关。有趣的是,在AppNLGF小鼠中,无髓轴突的密度显著降低,而谷氨酸能,GABA能,或p-tau181阳性轴突受影响较小。相反,在AppNLGF小鼠中,p-tau181阳性轴突周围的髓鞘显著减少.
    结论:这项研究表明,p-tau181信号与Aβ病理小鼠模型大脑中的小白蛋白阳性GABA能中间神经元的轴突共定位,髓鞘被破坏。
    The tau protein phosphorylated at Thr181 (p-tau181) in cerebrospinal fluid and blood is a sensitive biomarker for Alzheimer\'s disease (AD). Increased p-tau181 levels correlate well with amyloid-β (Aβ) pathology and precede neurofibrillary tangle formation in the early stage of AD; however, the relationship between p-tau181 and Aβ-mediated pathology is less well understood. We recently reported that p-tau181 represents axonal abnormalities in mice with Aβ pathology (AppNLGF). However, from which neuronal subtype(s) these p-tau181-positive axons originate remains elusive.
    The main purpose of this study is to differentiate neuronal subtype(s) and elucidate damage associated with p-tau181-positive axons by immunohistochemical analysis of AppNLGF mice brains.
    Colocalization between p-tau181 and (1) unmyelinated axons positive for vesicular acetylcholine transporter or norepinephrine transporter and (2) myelinated axons positive for vesicular glutamate transporter, vesicular GABA transporter, or parvalbumin in the brains of 24-month-old AppNLGF and control mice without Aβ pathology were analyzed. The density of these axons was also compared.
    Unmyelinated axons of cholinergic or noradrenergic neurons did not overlap with p-tau181. By contrast, p-tau181 signals colocalized with myelinated axons of parvalbumin-positive GABAergic interneurons but not of glutamatergic neurons. Interestingly, the density of unmyelinated axons was significantly decreased in AppNLGF mice, whereas that of glutamatergic, GABAergic, or p-tau181-positive axons was less affected. Instead, myelin sheaths surrounding p-tau181-positive axons were significantly reduced in AppNLGF mice.
    This study demonstrates that p-tau181 signals colocalize with axons of parvalbumin-positive GABAergic interneurons with disrupted myelin sheaths in the brains of a mouse model of Aβ pathology.
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  • 文章类型: Journal Article
    红藻酸盐型谷氨酸受体(KARs)在GABA能中间神经元中强烈表达,并具有通过离子型和G蛋白偶联机制调节其功能的能力。GABA能中间神经元对于新生儿和成人大脑协调网络活动的产生至关重要。然而,神经元间KAR在网络同步中的作用尚不清楚.这里,我们表明,在GABA能神经元中选择性缺乏GluK1KARs的新生小鼠的海马中,GABA能神经传递和自发网络活动受到干扰。神经元间GluK1KARs的内源性活动维持自发性新生儿网络爆发的频率和持续时间,并抑制其通过海马网络的传播。在成年雄性小鼠中,GABA能神经元中GluK1的缺失导致更强的海马伽马振荡和增强的theta-gamma交叉频率耦合,与巴恩斯迷宫中更快的空间再学习相吻合。在女性中,神经元间GluK1的丢失导致较短的尖锐波纹波振荡,并在灵活的测序任务中略微受损。此外,间神经元GluK1的消融导致较低的一般活动和新的对象回避,而只引起轻微的焦虑表型。这些数据表明,在不同发育阶段,GABA能中间神经元中含有GluK1的KAR在调节海马生理网络动力学中的关键作用。
    Kainate type glutamate receptors (KARs) are strongly expressed in GABAergic interneurons and have the capability of modulating their functions via ionotropic and G-protein coupled mechanisms. GABAergic interneurons are critical for generation of coordinated network activity in both neonatal and adult brain, yet the role of interneuronal KARs in network synchronization remains unclear. Here, we show that GABAergic neurotransmission and spontaneous network activity is perturbed in the hippocampus of neonatal mice lacking GluK1 KARs selectively in GABAergic neurons. Endogenous activity of interneuronal GluK1 KARs maintains the frequency and duration of spontaneous neonatal network bursts and restrains their propagation through the hippocampal network. In adult male mice, the absence of GluK1 in GABAergic neurons led to stronger hippocampal gamma oscillations and enhanced theta-gamma cross frequency coupling, coinciding with faster spatial relearning in the Barnes maze. In females, loss of interneuronal GluK1 resulted in shorter sharp wave ripple oscillations and slightly impaired abilities in flexible sequencing task. In addition, ablation of interneuronal GluK1 resulted in lower general activity and novel object avoidance, while causing only minor anxiety phenotype. These data indicate a critical role for GluK1 containing KARs in GABAergic interneurons in regulation of physiological network dynamics in the hippocampus at different stages of development.
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  • 文章类型: Journal Article
    尽管海马体通常被认为是空间表示的认知中心,学习,和记忆,越来越多的证据支持它在调节运动中的作用。然而,海马运动和探索行为调节的神经元机制仍不清楚。在这项研究中,我们发现,抑制性海马突触投射到内侧隔膜(MS)双向控制小鼠的运动速度。海马中MS投射中间神经元的激活或MS中海马起源的抑制性突触末端的激活降低了运动和探索行为。另一方面,MS中海马起源的抑制性突触末端的抑制增加了运动。与间隔突出的中间神经元不同,投射到脾后皮质的海马中间神经元的激活没有改变动物的运动。因此,这项研究揭示了在动物运动的调节中,从海马到内侧隔膜的特定长程抑制性突触输出。
    Although the hippocampus is generally considered a cognitive center for spatial representation, learning, and memory, increasing evidence supports its roles in regulating locomotion. However, the neuronal mechanisms of the hippocampal regulation of locomotion and exploratory behavior remain unclear. In this study, we found that the inhibitory hippocampal synaptic projection to the medial septum (MS) bi-directionally controls the locomotor speed of mice. The activation of the MS-projecting interneurons in the hippocampus or the activation of the hippocampus-originated inhibitory synaptic terminals in the MS decreased locomotion and exploratory behavior. On the other hand, the inhibition of the hippocampus-originated inhibitory synaptic terminals in the MS increased locomotion. Unlike the septal projecting interneurons, the activation of the hippocampal interneurons projecting to the retrosplenial cortex did not change animal locomotion. Therefore, this study reveals a specific long-range inhibitory synaptic output from the hippocampus to the medial septum in the regulation of animal locomotion.
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  • 文章类型: Journal Article
    恐惧学习和记忆依赖于构成前额叶皮层的兴奋性和抑制性神经元群体之间的动态相互作用,杏仁核,和海马回路。而GABA能神经元对兴奋性主细胞(PC)的抑制作用会抑制其兴奋,GABA能神经元的抑制通过称为去抑制的过程促进PCs的兴奋。具体来说,表达小白蛋白(PV)和生长抑素(SOM)的GABA能中间神经元对PC的不同亚细胞结构域提供抑制作用,而表达血管活性肠多肽(VIP)的那些通过抑制PV和SOM中间神经元来促进PC的抑制。重要的是,尽管PV+的主要连接主题和底层网络功能,SOM+,VIP+中间神经元在皮质和边缘区域复制,这些抑制性群体在恐惧学习和记忆中起着特定区域的作用.这里,我们概述了杏仁核的恐惧过程,海马体,和前额叶皮层基于在人类和动物研究中获得的证据。此外,关注使用遗传定义的成像和干预策略获得的最新发现,我们讨论了PV+的特定于种群的函数,SOM+,和恐惧回路中的VIP+中间神经元。最后,我们回顾了当前的见解,这些见解将特定区域的抑制和去抑制网络模式整合到恐惧记忆获取和恐惧相关疾病中。
    Fear learning and memory rely on dynamic interactions between the excitatory and inhibitory neuronal populations that make up the prefrontal cortical, amygdala, and hippocampal circuits. Whereas inhibition of excitatory principal cells (PCs) by GABAergic neurons restrains their excitation, inhibition of GABAergic neurons promotes the excitation of PCs through a process called disinhibition. Specifically, GABAergic interneurons that express parvalbumin (PV+) and somatostatin (SOM+) provide inhibition to different subcellular domains of PCs, whereas those that express the vasoactive intestinal polypeptide (VIP+) facilitate disinhibition of PCs by inhibiting PV+ and SOM+ interneurons. Importantly, although the main connectivity motifs and the underlying network functions of PV+, SOM+, and VIP+ interneurons are replicated across cortical and limbic areas, these inhibitory populations play region-specific roles in fear learning and memory. Here, we provide an overview of the fear processing in the amygdala, hippocampus, and prefrontal cortex based on the evidence obtained in human and animal studies. Moreover, focusing on recent findings obtained using genetically defined imaging and intervention strategies, we discuss the population-specific functions of PV+, SOM+, and VIP+ interneurons in fear circuits. Last, we review current insights that integrate the region-specific inhibitory and disinhibitory network patterns into fear memory acquisition and fear-related disorders.
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  • 文章类型: Journal Article
    神经调节蛋白(NRGs)通过ErbB受体信号调节神经发育,兴奋性,突触和网络活动,以及与精神疾病相关的行为。NRG2/ErbB4和NMDA受体之间的双向信号传导被认为响应于增加的兴奋性神经传递或升高的细胞外谷氨酸水平而稳态调节GABA能中间神经元。未加工的proNRG2在细胞体和近端树突上形成离散的簇,与钾通道Kv2.1在专门的内质网-质膜(ER-PM)连接处共定位,和NMDA受体激活触发从ER-PM连接的快速解离和通过ADAM10的胞外域脱落。这里,我们阐明了proNRG2在ER-PM连接处聚集及其通过NMDA受体调节的机制基础。重要的是,我们证明proNRG2通过直接结合ER-驻留膜系链VAP促进ER-PM连接的形成,像Kv2.1.proNRG2细胞内结构域包含两个非规范的,协同介导VAP结合的低亲和力位点。其中之一是在NMDA受体激活后去磷酸化的隐匿性和磷酸化依赖性VAP结合基序,从而揭示兴奋性神经传递如何促进proNRG2从ER-PM连接的解离。因此,proNRG2和Kv2.1可以独立地充当神经元ER-PM连接的VAP依赖性组织者。基于这些和先前的研究,我们建议proNRG2和Kv2.1作为NMDA受体的共同调节下游效应子,以稳态调节GABA能中间神经元。
    Neuregulins (NRGs) signal via ErbB receptors to regulate neural development, excitability, synaptic and network activity, and behaviors relevant to psychiatric disorders. Bidirectional signaling between NRG2/ErbB4 and NMDA receptors is thought to homeostatically regulate GABAergic interneurons in response to increased excitatory neurotransmission or elevated extracellular glutamate levels. Unprocessed proNRG2 forms discrete clusters on cell bodies and proximal dendrites that colocalize with the potassium channel Kv2.1 at specialized endoplasmic reticulum-plasma membrane (ER-PM) junctions, and NMDA receptor activation triggers rapid dissociation from ER-PM junctions and ectodomain shedding by ADAM10. Here, we elucidate the mechanistic basis of proNRG2 clustering at ER-PM junctions and its regulation by NMDA receptors. Importantly, we demonstrate that proNRG2 promotes the formation of ER-PM junctions by directly binding the ER-resident membrane tether VAP, like Kv2.1. The proNRG2 intracellular domain harbors two non-canonical, low-affinity sites that cooperatively mediate VAP binding. One of these is a cryptic and phosphorylation-dependent VAP binding motif that is dephosphorylated following NMDA receptor activation, thus revealing how excitatory neurotransmission promotes the dissociation of proNRG2 from ER-PM junctions. Therefore, proNRG2 and Kv2.1 can independently function as VAP-dependent organizers of neuronal ER-PM junctions. Based on these and prior studies, we propose that proNRG2 and Kv2.1 serve as co-regulated downstream effectors of NMDA receptors to homeostatically regulate GABAergic interneurons.
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  • 文章类型: Journal Article
    伴有自杀行为的重度抑郁症(sMDD)是一种服务器情绪障碍,给家庭和社会带来巨大负担。尽管在sMDD患者的死后组织中观察到γ-氨基丁酸(GABA)水平降低,GABA水平改变的分子机制仍然难以捉摸。在这项研究中,我们从5例sMDD患者中产生了诱导多能干细胞(iPSC),并将iPSC分化为GABA能中间神经元(GINs)和腹侧前脑类器官.sMDDGINs表现出神经元形态改变和神经放电增加,以及减弱的钙信号传播,与对照组相比。转录组测序显示,5-羟色胺能受体2C(5-HT2C)的表达降低可能会导致sMDD中神经元活性缺陷。此外,靶向5-HT2C受体,使用小分子激动剂或遗传方法,恢复sMDDGINs的神经元活性缺陷。我们的发现为研究sMDD的分子机制和药物发现提供了人类细胞模型。
    Major depressive disorder with suicide behavior (sMDD) is a server mood disorder, bringing tremendous burden to family and society. Although reduced gamma amino butyric acid (GABA) level has been observed in postmortem tissues of sMDD patients, the molecular mechanism by which GABA levels are altered remains elusive. In this study, we generated induced pluripotent stem cells (iPSC) from five sMDD patients and differentiated the iPSCs to GABAergic interneurons (GINs) and ventral forebrain organoids. sMDD GINs exhibited altered neuronal morphology and increased neural firing, as well as weakened calcium signaling propagation, compared with controls. Transcriptomic sequencing revealed that a decreased expression of serotoninergic receptor 2C (5-HT2C) may cause the defected neuronal activity in sMDD. Furthermore, targeting 5-HT2C receptor, using a small molecule agonist or genetic approach, restored neuronal activity deficits in sMDD GINs. Our findings provide a human cellular model for studying the molecular mechanisms and drug discoveries for sMDD.
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