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Glycinergic Transmission in the Presence and Absence of Functional GlyT2: Lessons From the Auditory Brainstem. 功能GlyT2存在和缺失时的甘氨酸能传递:来自听觉脑干的启示。
IF 3.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2021-02-09 eCollection Date: 2020-01-01 DOI: 10.3389/fnsyn.2020.560008
Sina E Brill, Ayse Maraslioglu, Catharina Kurz, Florian Kramer, Martin F Fuhr, Abhyudai Singh, Eckhard Friauf

Synaptic transmission is controlled by re-uptake systems that reduce transmitter concentrations in the synaptic cleft and recycle the transmitter into presynaptic terminals. The re-uptake systems are thought to ensure cytosolic concentrations in the terminals that are sufficient for reloading empty synaptic vesicles (SVs). Genetic deletion of glycine transporter 2 (GlyT2) results in severely disrupted inhibitory neurotransmission and ultimately to death. Here we investigated the role of GlyT2 at inhibitory glycinergic synapses in the mammalian auditory brainstem. These synapses are tuned for resilience, reliability, and precision, even during sustained high-frequency stimulation when endocytosis and refilling of SVs probably contribute substantially to efficient replenishment of the readily releasable pool (RRP). Such robust synapses are formed between MNTB and LSO neurons (medial nucleus of the trapezoid body, lateral superior olive). By means of patch-clamp recordings, we assessed the synaptic performance in controls, in GlyT2 knockout mice (KOs), and upon acute pharmacological GlyT2 blockade. Via computational modeling, we calculated the reoccupation rate of empty release sites and RRP replenishment kinetics during 60-s challenge and 60-s recovery periods. Control MNTB-LSO inputs maintained high fidelity neurotransmission at 50 Hz for 60 s and recovered very efficiently from synaptic depression. During 'marathon-experiments' (30,600 stimuli in 20 min), RRP replenishment accumulated to 1,260-fold. In contrast, KO inputs featured severe impairments. For example, the input number was reduced to ~1 (vs. ~4 in controls), implying massive functional degeneration of the MNTB-LSO microcircuit and a role of GlyT2 during synapse maturation. Surprisingly, neurotransmission did not collapse completely in KOs as inputs still replenished their small RRP 80-fold upon 50 Hz | 60 s challenge. However, they totally failed to do so for extended periods. Upon acute pharmacological GlyT2 inactivation, synaptic performance remained robust, in stark contrast to KOs. RRP replenishment was 865-fold in marathon-experiments, only ~1/3 lower than in controls. Collectively, our empirical and modeling results demonstrate that GlyT2 re-uptake activity is not the dominant factor in the SV recycling pathway that imparts indefatigability to MNTB-LSO synapses. We postulate that additional glycine sources, possibly the antiporter Asc-1, contribute to RRP replenishment at these high-fidelity brainstem synapses.

突触传递由再摄取系统控制,该系统降低突触间隙中的递质浓度并将递质再循环到突触前末端。再摄取系统被认为确保了末端的细胞质浓度足以重新装载空突触囊泡(SVs)。甘氨酸转运蛋白2 (GlyT2)的基因缺失导致抑制性神经传递严重中断,最终导致死亡。在这里,我们研究了GlyT2在哺乳动物听觉脑干中抑制性甘氨酸能突触中的作用。即使在持续的高频刺激下,当内吞作用和sv的再填充可能有助于有效地补充易释放池(RRP)时,这些突触也被调整为弹性、可靠性和准确性。这种强大的突触在MNTB和LSO神经元(梯形体内侧核,外侧上橄榄)之间形成。通过膜片钳记录,我们评估了对照组、GlyT2敲除小鼠(KOs)和急性GlyT2药物阻断小鼠的突触表现。通过计算模型,我们计算了60-s挑战和60-s恢复期间空释放位点的再占用率和RRP补充动力学。对照MNTB-LSO输入在50 Hz下维持高保真神经传递60 s,并能非常有效地从突触抑制中恢复。在“马拉松实验”中(20分钟30600次刺激),RRP补充累积到1260倍。相比之下,KO输入具有严重的损伤。例如,输入数量减少到~1(对照组为~4),这意味着MNTB-LSO微电路的大量功能退化以及GlyT2在突触成熟过程中的作用。令人惊讶的是,神经传递并没有完全崩溃,因为输入仍然在50 Hz / 60 s的挑战下补充其小RRP 80倍。然而,他们在很长一段时间内完全没有这样做。在急性GlyT2药理学失活后,突触表现仍然强劲,与KOs形成鲜明对比。在马拉松实验中,RRP补充量是对照组的865倍,仅比对照组低1/3。总的来说,我们的实证和建模结果表明,GlyT2再摄取活性并不是赋予MNTB-LSO突触不疲劳性的SV再循环途径的主导因素。我们假设额外的甘氨酸来源,可能是反转运蛋白Asc-1,有助于这些高保真脑干突触的RRP补充。
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引用次数: 8
Cyfip1 Regulates SynGAP1 at Hippocampal Synapses. Cyfip1调控海马突触SynGAP1。
IF 3.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2021-02-05 eCollection Date: 2020-01-01 DOI: 10.3389/fnsyn.2020.581714
Abhishek Sahasrabudhe, Fatema Begum, Christopher A Guevara, Chenel Morrison, Kuangfu Hsiao, Nebojsa Kezunovic, Ozlem Bozdagi-Gunal, Deanna L Benson

In humans, copy number variations in CYFIP1 appear to have sweeping physiological and structural consequences in the brain, either producing or altering the severity of intellectual disability, autism, and schizophrenia. Independently, SynGAP1 haploinsufficiency produces intellectual disability and, frequently, autism. Cyfip1 inhibits protein translation and promotes actin polymerization, and SynGAP1 is a synaptically localized Ras/Rap GAP. While these proteins are clearly distinct, studies investigating their functions in mice have shown that each regulates the maturation of synapses in the hippocampus and haploinsufficiency for either produces an exaggerated form of mGluR-dependent long-term depression, suggesting that some signaling pathways converge. In this study, we examined how Cyfip1 haploinsufficiency impacts SynGAP1 levels and localization, as well as potential sites for mechanistic interaction in mouse hippocampus. The data show that synaptic, but not total, levels of SynGAP1 in Cyfip1 +/- mice were abnormally low during early postnatal development and in adults. This may be in response to a shift in the balance of kinases that activate SynGAP1 as levels of Cdk5 were reduced and those of activated CaMKII were maintained in Cyfip1 +/- mice compared to wild-type mice. Alternatively, this could reflect altered actin dynamics as Rac1 activity in Cyfip1 +/- hippocampus was boosted significantly compared to wild-type mice, and levels of synaptic F-actin were generally enhanced due in part to an increase in the activity of the WAVE regulatory complex. Decreased synaptic SynGAP1 coupled with a CaMKII-mediated bias toward Rap1 inactivation at synapses is also consistent with increased levels of synaptic GluA2, increased AMPA receptor-mediated responses to stimulation, and increased levels of synaptic mGluR1/5 compared to wild-type mice. Collectively, our data suggest that Cyfip1 regulates SynGAP1 and the two proteins work coordinately at synapses to appropriately direct actin polymerization and GAP activity.

在人类中,CYFIP1的拷贝数变异似乎在大脑中具有广泛的生理和结构后果,产生或改变智力残疾、自闭症和精神分裂症的严重程度。独立地说,SynGAP1单倍不足会导致智力残疾,并经常导致自闭症。Cyfip1抑制蛋白翻译并促进肌动蛋白聚合,SynGAP1是突触定位的Ras/Rap GAP。虽然这些蛋白明显不同,但在小鼠中研究它们的功能的研究表明,每一种蛋白都能调节海马突触的成熟,任何一种蛋白的单倍不足都会产生一种夸大形式的mglur依赖的长期抑郁,这表明一些信号通路会聚在一起。在这项研究中,我们研究了Cyfip1单倍不足如何影响SynGAP1水平和定位,以及小鼠海马中机制相互作用的潜在位点。数据显示,在Cyfip1 +/-小鼠的突触(而非总)SynGAP1水平在出生后早期发育和成年期间异常低。这可能是由于与野生型小鼠相比,在Cyfip1 +/-小鼠中,激活SynGAP1的激酶平衡发生了变化,因为Cdk5水平降低,而激活的CaMKII水平保持不变。或者,这可能反映了肌动蛋白动力学的改变,因为与野生型小鼠相比,Cyfip1 +/-海马中的Rac1活性显著增强,突触f -肌动蛋白水平普遍增强,部分原因是WAVE调节复合物活性的增加。与野生型小鼠相比,突触SynGAP1的减少加上camkii介导的突触对Rap1失活的偏向,也与突触GluA2水平的增加、AMPA受体介导的刺激反应增加以及突触mGluR1/5水平的增加相一致。总的来说,我们的数据表明Cyfip1调节SynGAP1,这两个蛋白在突触上协调工作,适当地指导肌动蛋白聚合和GAP活性。
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引用次数: 3
Five Hours Total Sleep Deprivation Does Not Affect CA1 Dendritic Length or Spine Density 五小时完全睡眠剥夺不会影响CA1树突长度或脊柱密度
IF 3.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2021-02-05 DOI: 10.1101/2021.02.04.429550
Alvin T S Brodin, Sarolta Gabulya, K. Wellfelt, Tobias E Karlsson
Sleep is essential for long term memory function. However the neuroanatomical consequences of sleep loss are disputed. Sleep deprivation has been reported to cause both decreases and increases of dendritic spine density. Here we use Thy1-GFP expressing transgenic mice to investigate the effects of acute sleep deprivation on the dendritic architecture of hippocampal CA1 pyramidal neurons. We found that five hours of sleep deprivation had no effect on either dendritic length or dendritic spine density. Our work suggests that no major neuroanatomical changes result from one episode of sleep deprivation.
睡眠对长期记忆功能至关重要。然而,睡眠不足的神经解剖学后果存在争议。据报道,睡眠不足会导致树突棘密度下降和增加。在这里,我们使用表达Thy1-GFP的转基因小鼠来研究急性睡眠剥夺对海马CA1锥体神经元树突结构的影响。我们发现,五个小时的睡眠剥夺对树突长度或树突棘密度都没有影响。我们的研究表明,一次睡眠不足不会导致重大的神经解剖学变化。
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引用次数: 1
Increased Excitability and Heightened Magnitude of Long-Term Potentiation at Hippocampal CA3-CA1 Synapses in a Mouse Model of Neonatal Hyperoxia Exposure. 新生儿高氧暴露小鼠模型中海马 CA3-CA1 突触的兴奋性增加和长期电位的幅度增大
IF 2.8 4区 医学 Q2 NEUROSCIENCES Pub Date : 2021-01-06 eCollection Date: 2020-01-01 DOI: 10.3389/fnsyn.2020.609903
Manimaran Ramani, Kiara Miller, Namasivayam Ambalavanan, Lori L McMahon

Preterm infants exposed to supraphysiological oxygen (hyperoxia) during the neonatal period have hippocampal atrophy and cognitive dysfunction later in childhood and as adolescents. Previously, we reported that 14-week-old adult mice exposed to hyperoxia as newborns had spatial memory deficits and hippocampal shrinkage, findings that mirror those of human adolescents who were born preterm. The area CA1 region of the hippocampus that is crucial for spatial learning and memory is highly vulnerable to oxidative stress. In this study, we investigated the long-term impact of neonatal hyperoxia exposure on hippocampal CA3-CA1 synaptic function. Male and female C57BL/6J mouse pups were continuously exposed to either 85% normobaric oxygen or air between postnatal days 2-14. Hippocampal slice electrophysiology at CA3-CA1 synapses was then performed at 14 weeks of age. We observed that hyperoxia exposed mice have heightened strength of basal synaptic transmission measured in input-output curves, increased fiber volley amplitude indicating increased axonal excitability, and heightened LTP magnitude at CA3-CA1 synapses, likely a consequence of increased postsynaptic depolarization during tetanus. These data demonstrate that supraphysiological oxygen exposure during the critical neonatal developmental period leads to pathologically heightened CA3-CA1 synaptic function during early adulthood which may contribute to hippocampal shrinkage and learning and memory deficits we previously reported. Furthermore, these results will help shed light on the consequences of hyperoxia exposure on the development of hippocampal synaptic circuit abnormalities that could be contributing to cognitive deficits in children born preterm.

早产儿在新生儿期暴露于超生理氧(高氧)环境中,会导致海马萎缩,并在儿童期和青少年期出现认知功能障碍。此前,我们曾报道,14 周大的成年小鼠在刚出生时暴露于高氧环境,会出现空间记忆障碍和海马萎缩,这些发现与早产青少年的情况如出一辙。对空间学习和记忆至关重要的海马 CA1 区极易受到氧化应激的影响。在这项研究中,我们调查了新生儿高氧暴露对海马 CA3-CA1 突触功能的长期影响。雌雄C57BL/6J幼鼠在出生后第2-14天连续暴露于85%常压氧或空气中。然后在14周龄时对CA3-CA1突触进行海马切片电生理学研究。我们观察到,根据输入-输出曲线测量,暴露于高氧环境的小鼠基础突触传递强度增加,纤维波动幅度增加,表明轴突兴奋性增加,CA3-CA1突触的LTP幅度增加,这可能是破伤风期间突触后去极化增加的结果。这些数据表明,在新生儿发育的关键时期,超生理氧暴露会导致成年早期 CA3-CA1 突触功能的病理性增强,这可能是我们之前报道的海马缩小以及学习和记忆缺陷的原因。此外,这些结果将有助于揭示高氧暴露对海马突触回路异常发展的影响,而这种异常可能会导致早产儿的认知障碍。
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引用次数: 0
A Picture Worth a Thousand Molecules-Integrative Technologies for Mapping Subcellular Molecular Organization and Plasticity in Developing Circuits. 一张图片胜过千百个分子--绘制发育中电路的亚细胞分子组织和可塑性的集成技术》(A Picture Worth a Thousand Molecules-Integrative Technologies for Mapping Sub-cellular Molecular Organization and Plasticity in Developing Circuits)。
IF 3.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2021-01-05 eCollection Date: 2020-01-01 DOI: 10.3389/fnsyn.2020.615059
Jacqueline A Minehart, Colenso M Speer

A key challenge in developmental neuroscience is identifying the local regulatory mechanisms that control neurite and synaptic refinement over large brain volumes. Innovative molecular techniques and high-resolution imaging tools are beginning to reshape our view of how local protein translation in subcellular compartments drives axonal, dendritic, and synaptic development and plasticity. Here we review recent progress in three areas of neurite and synaptic study in situ-compartment-specific transcriptomics/translatomics, targeted proteomics, and super-resolution imaging analysis of synaptic organization and development. We discuss synergies between sequencing and imaging techniques for the discovery and validation of local molecular signaling mechanisms regulating synaptic development, plasticity, and maintenance in circuits.

发育神经科学的一个关键挑战是确定控制大脑部神经元和突触细化的局部调控机制。创新的分子技术和高分辨率成像工具开始重塑我们对亚细胞区局部蛋白质翻译如何驱动轴突、树突和突触发育和可塑性的看法。在此,我们回顾了神经元和突触原位研究的三个领域的最新进展--特异性分区转录组学/翻译组学、靶向蛋白质组学以及突触组织和发育的超分辨率成像分析。我们讨论了测序和成像技术在发现和验证调节突触发育、可塑性和回路维持的局部分子信号机制方面的协同作用。
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引用次数: 0
Calcium Sensors STIM1 and STIM2 Regulate Different Calcium Functions in Cultured Hippocampal Neurons. 钙传感器STIM1和STIM2调节培养海马神经元不同钙功能。
IF 3.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2021-01-05 eCollection Date: 2020-01-01 DOI: 10.3389/fnsyn.2020.573714
Liliya Kushnireva, Eduard Korkotian, Menahem Segal

There are growing indications for the involvement of calcium stores in the plastic properties of neurons and particularly in dendritic spines of central neurons. The store-operated calcium entry (SOCE) channels are assumed to be activated by the calcium sensor stromal interaction molecule (STIM)which leads to activation of its associated Orai channel. There are two STIM species, and the differential role of the two in SOCE is not entirely clear. In the present study, we were able to distinguish between transfected STIM1, which is more mobile primarily in young neurons, and STIM2 which is less mobile and more prominent in older neurons in culture. STIM1 mobility is associated with spontaneous calcium sparks, local transient rise in cytosolic [Ca2+]i, and in the formation and elongation of dendritic filopodia/spines. In contrast, STIM2 is associated with older neurons, where it is mobile and moves into dendritic spines primarily when cytosolic [Ca2+]i levels are reduced, apparently to activate resident Orai channels. These results highlight a role for STIM1 in the regulation of [Ca2+]i fluctuations associated with the formation of dendritic spines or filopodia in the developing neuron, whereas STIM2 is associated with the maintenance of calcium entry into stores in the adult neuron.

越来越多的迹象表明,钙的储存与神经元的可塑性有关,特别是与中枢神经元的树突棘有关。储存操作钙进入(SOCE)通道被钙传感器基质相互作用分子(STIM)激活,从而导致其相关的Orai通道被激活。有两种STIM,两者在SOCE中的不同作用尚不完全清楚。在目前的研究中,我们能够区分转染的STIM1和STIM2,前者主要在年轻神经元中更具移动性,后者在培养的老年神经元中移动性较差,但更突出。STIM1迁移率与自发钙火花、细胞质[Ca2+]i的局部瞬时升高以及树突丝状足/棘的形成和伸长有关。相反,STIM2与较老的神经元有关,当细胞质[Ca2+]i水平降低时,STIM2是可移动的,主要移动到树突棘中,显然是为了激活常驻的Orai通道。这些结果强调了STIM1在调节与发育中的神经元树突棘或丝状足形成相关的[Ca2+]i波动中的作用,而STIM2与维持钙进入成年神经元中的储存有关。
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引用次数: 9
Relevance of Cortical and Hippocampal Interneuron Functional Diversity to General Anesthetic Mechanisms: A Narrative Review. 皮质和海马中间神经元功能多样性与全身麻醉机制的相关性:叙述性综述。
IF 3.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2021-01-01 DOI: 10.3389/fnsyn.2021.812905
Iris A Speigel, Hugh C Hemmings

General anesthetics disrupt brain processes involved in consciousness by altering synaptic patterns of excitation and inhibition. In the cerebral cortex and hippocampus, GABAergic inhibition is largely mediated by inhibitory interneurons, a heterogeneous group of specialized neuronal subtypes that form characteristic microcircuits with excitatory neurons. Distinct interneuron subtypes regulate specific excitatory neuron networks during normal behavior, but how these interneuron subtypes are affected by general anesthetics is unclear. This narrative review summarizes current principles of the synaptic architecture of cortical and interneuron subtypes, their contributions to different forms of inhibition, and their roles in distinct neuronal microcircuits. The molecular and cellular targets in these circuits that are sensitive to anesthetics are reviewed in the context of how anesthetics impact interneuron function in a subtype-specific manner. The implications of this functional interneuron diversity for mechanisms of anesthesia are discussed, as are their implications for anesthetic-induced changes in neural plasticity and overall brain function.

全身麻醉剂通过改变突触的兴奋和抑制模式来破坏与意识有关的大脑过程。在大脑皮层和海马中,gaba能抑制主要由抑制性中间神经元介导,抑制性中间神经元是一组异质的特化神经元亚型,与兴奋性神经元形成特征性微回路。在正常行为中,不同的中间神经元亚型调节特定的兴奋性神经元网络,但这些中间神经元亚型如何受到全身麻醉剂的影响尚不清楚。本文综述了皮层和中间神经元亚型突触结构的当前原理,它们对不同形式的抑制的贡献,以及它们在不同神经元微回路中的作用。在麻醉药如何以亚型特异性方式影响中间神经元功能的背景下,对这些回路中对麻醉药敏感的分子和细胞靶点进行了综述。讨论了这种功能性中间神经元多样性对麻醉机制的影响,以及它们对麻醉诱导的神经可塑性和整体脑功能变化的影响。
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引用次数: 2
Endocannabinoid-Like Lipid Neuromodulators in the Regulation of Dopamine Signaling: Relevance for Drug Addiction. 内源性大麻素样脂质神经调节剂在多巴胺信号调节中的作用:与药物成瘾相关。
IF 3.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2020-12-23 eCollection Date: 2020-01-01 DOI: 10.3389/fnsyn.2020.588660
Claudia Sagheddu, Larissa Helena Torres, Tania Marcourakis, Marco Pistis

The family of lipid neuromodulators has been rapidly growing, as the use of different -omics techniques led to the discovery of a large number of naturally occurring N-acylethanolamines (NAEs) and N-acyl amino acids belonging to the complex lipid signaling system termed endocannabinoidome. These molecules exert a variety of biological activities in the central nervous system, as they modulate physiological processes in neurons and glial cells and are involved in the pathophysiology of neurological and psychiatric disorders. Their effects on dopamine cells have attracted attention, as dysfunctions of dopamine systems characterize a range of psychiatric disorders, i.e., schizophrenia and substance use disorders (SUD). While canonical endocannabinoids are known to regulate excitatory and inhibitory synaptic inputs impinging on dopamine cells and modulate several dopamine-mediated behaviors, such as reward and addiction, the effects of other lipid neuromodulators are far less clear. Here, we review the emerging role of endocannabinoid-like neuromodulators in dopamine signaling, with a focus on non-cannabinoid N-acylethanolamines and their receptors. Mounting evidence suggests that these neuromodulators contribute to modulate synaptic transmission in dopamine regions and might represent a target for novel medications in alcohol and nicotine use disorder.

随着不同组学技术的使用,发现了大量天然存在的n -酰基乙醇胺(NAEs)和n -酰基氨基酸,这些氨基酸属于复杂的脂质信号系统,称为内源性大麻素组(endocannabinoidome),脂质神经调节剂家族正在迅速发展。这些分子在中枢神经系统中发挥多种生物活性,因为它们调节神经元和神经胶质细胞的生理过程,并参与神经和精神疾病的病理生理学。它们对多巴胺细胞的影响引起了人们的关注,因为多巴胺系统功能障碍是一系列精神疾病的特征,即精神分裂症和物质使用障碍(SUD)。虽然已知典型的内源性大麻素可以调节多巴胺细胞的兴奋性和抑制性突触输入,并调节几种多巴胺介导的行为,如奖励和成瘾,但其他脂质神经调节剂的作用远不清楚。在这里,我们回顾了内源性大麻素样神经调节剂在多巴胺信号传导中的新作用,重点是非大麻素n-酰基乙醇胺及其受体。越来越多的证据表明,这些神经调节剂有助于调节多巴胺区域的突触传递,可能是治疗酒精和尼古丁使用障碍的新型药物的靶点。
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引用次数: 11
Clmp Regulates AMPA and Kainate Receptor Responses in the Neonatal Hippocampal CA3 and Kainate Seizure Susceptibility in Mice. Clmp调节小鼠新生海马CA3中AMPA和盐酸盐受体反应和盐酸盐癫痫易感性。
IF 3.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2020-12-21 eCollection Date: 2020-01-01 DOI: 10.3389/fnsyn.2020.567075
Seil Jang, Esther Yang, Doyoun Kim, Hyun Kim, Eunjoon Kim

Synaptic adhesion molecules regulate synapse development through trans-synaptic adhesion and assembly of diverse synaptic proteins. Many synaptic adhesion molecules positively regulate synapse development; some, however, exert negative regulation, although such cases are relatively rare. In addition, synaptic adhesion molecules regulate the amplitude of post-synaptic receptor responses, but whether adhesion molecules can regulate the kinetic properties of post-synaptic receptors remains unclear. Here we report that Clmp, a homophilic adhesion molecule of the Ig domain superfamily that is abundantly expressed in the brain, reaches peak expression at a neonatal stage (week 1) and associates with subunits of AMPA receptors (AMPARs) and kainate receptors (KARs). Clmp deletion in mice increased the frequency and amplitude of AMPAR-mediated miniature excitatory post-synaptic currents (mEPSCs) and the frequency, amplitude, and decay time constant of KAR-mediated mEPSCs in hippocampal CA3 neurons. Clmp deletion had minimal impacts on evoked excitatory synaptic currents at mossy fiber-CA3 synapses but increased extrasynaptic KAR, but not AMPAR, currents, suggesting that Clmp distinctly inhibits AMPAR and KAR responses. Behaviorally, Clmp deletion enhanced novel object recognition and susceptibility to kainate-induced seizures, without affecting contextual or auditory cued fear conditioning or pattern completion-based contextual fear conditioning. These results suggest that Clmp negatively regulates hippocampal excitatory synapse development and AMPAR and KAR responses in the neonatal hippocampal CA3 as well as object recognition and kainate seizure susceptibility in mice.

突触粘附分子通过跨突触粘附和多种突触蛋白的组装来调节突触的发育。许多突触粘附分子积极调节突触发育;然而,也有一些国家实行负面监管,尽管这种情况相对较少。此外,突触粘附分子调节突触后受体反应的幅度,但粘附分子是否能调节突触后受体的动力学性质尚不清楚。Clmp是一种在大脑中大量表达的Ig结构域超家族的亲同质粘附分子,在新生儿期(第1周)达到表达高峰,并与AMPA受体(AMPARs)和盐酸盐受体(KARs)亚基相关。小鼠Clmp缺失增加了ampar介导的微型兴奋性突触后电流(mEPSCs)的频率和振幅以及海马CA3神经元中kar介导的mEPSCs的频率、振幅和衰减时间常数。Clmp缺失对苔藓纤维- ca3突触诱发的兴奋性突触电流的影响最小,但增加了突触外KAR电流,而不是AMPAR电流,这表明Clmp明显抑制AMPAR和KAR反应。在行为上,Clmp缺失增强了对新物体的识别和对盐引起的癫痫发作的易感性,而不影响情境或听觉暗示的恐惧条件反射或基于模式完成的情境恐惧条件反射。这些结果表明,Clmp负性调节小鼠海马兴奋性突触发育、新生儿海马CA3的AMPAR和KAR反应以及物体识别和盐酸盐发作易感性。
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引用次数: 4
SynapsEM: Computer-Assisted Synapse Morphometry. SynapsEM:计算机辅助突触形态测定法。
IF 3.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2020-12-18 eCollection Date: 2020-01-01 DOI: 10.3389/fnsyn.2020.584549
Shigeki Watanabe, M Wayne Davis, Grant F Kusick, Janet Iwasa, Erik M Jorgensen

The structural features of a synapse help determine its function. Synapses are extremely small and tightly packed with vesicles and other organelles. Visualizing synaptic structure requires imaging by electron microscopy, and the features in micrographs must be quantified, a process called morphometry. Three parameters are typically assessed from each specimen: (1) the sizes of individual vesicles and organelles; (2) the absolute number and densities of organelles; and (3) distances between organelles and key features at synapses, such as active zone membranes and dense projections. For data to be meaningful, the analysis must be repeated from hundreds to thousands of images from several biological replicates, a daunting task. Here we report a custom computer program to analyze key structural features of synapses: SynapsEM. In short, we developed ImageJ/Fiji macros to record x,y-coordinates of segmented structures. The coordinates are then exported as text files. Independent investigators can reload the images and text files to reexamine the segmentation using ImageJ. The Matlab program then calculates and reports key synaptic parameters from the coordinates. Since the values are calculated from coordinates, rather than measured from each micrograph, other parameters such as locations of docked vesicles relative to the center of an active zone can be extracted in Matlab by additional scripting. Thus, this program can accelerate the morphometry of synapses and promote a more comprehensive analysis of synaptic ultrastructure.

突触的结构特征有助于决定它的功能。突触非常小,紧密地包裹着囊泡和其他细胞器。可视化突触结构需要电子显微镜成像,显微照片中的特征必须被量化,这一过程称为形态测量。通常从每个标本中评估三个参数:(1)单个囊泡和细胞器的大小;(2)细胞器的绝对数量和密度;(3)突触上的细胞器和关键特征之间的距离,如活性区膜和密集突起。为了使数据有意义,必须对来自几个生物复制的数百到数千张图像进行重复分析,这是一项艰巨的任务。在这里,我们报告一个自定义的计算机程序来分析突触的关键结构特征:SynapsEM。简而言之,我们开发了ImageJ/Fiji宏来记录分割结构的x、y坐标。然后将坐标导出为文本文件。独立研究人员可以重新加载图像和文本文件,使用ImageJ重新检查分割。然后Matlab程序根据坐标计算并报告关键的突触参数。由于这些值是根据坐标计算的,而不是从每张显微照片中测量的,因此可以通过额外的脚本在Matlab中提取其他参数,例如停靠的囊泡相对于活动区域中心的位置。因此,该程序可以加速突触的形态测定,促进对突触超微结构的更全面的分析。
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引用次数: 14
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Frontiers in Synaptic Neuroscience
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