IF 14.7 1区医学

Neuron Pub Date : 2024-10-23 Epub Date: 2024-08-22 DOI: 10.1016/j.neuron.2024.07.023

William E Snyder, Petra E Vértes, Vanessa Kyriakopoulou, Konrad Wagstyl, Logan Z J Williams, Dustin Moraczewski, Adam G Thomas, Vyacheslav R Karolis, Jakob Seidlitz, Denis Rivière, Emma C Robinson, Jean-Francois Mangin, Armin Raznahan, Edward T Bullmore

{"title":"A bimodal taxonomy of adult human brain sulcal morphology related to timing of fetal sulcation and trans-sulcal gene expression gradients.","authors":"William E Snyder, Petra E Vértes, Vanessa Kyriakopoulou, Konrad Wagstyl, Logan Z J Williams, Dustin Moraczewski, Adam G Thomas, Vyacheslav R Karolis, Jakob Seidlitz, Denis Rivière, Emma C Robinson, Jean-Francois Mangin, Armin Raznahan, Edward T Bullmore","doi":"10.1016/j.neuron.2024.07.023","DOIUrl":"10.1016/j.neuron.2024.07.023","url":null,"abstract":"We developed a computational pipeline (now provided as a resource) for measuring morphological similarity between cortical surface sulci to construct a sulcal phenotype network (SPN) from each magnetic resonance imaging (MRI) scan in an adult cohort (n = 34,725; 45-82 years). Networks estimated from pairwise similarities of 40 sulci on 5 morphological metrics comprised two clusters of sulci, represented also by the bimodal distribution of sulci on a linear-to-complex dimension. Linear sulci were more heritable and typically located in unimodal cortex, and complex sulci were less heritable and typically located in heteromodal cortex. Aligning these results with an independent fetal brain MRI cohort (n = 228; 21-36 gestational weeks), we found that linear sulci formed earlier, and the earliest and latest-forming sulci had the least between-adult variation. Using high-resolution maps of cortical gene expression, we found that linear sulcation is mechanistically underpinned by trans-sulcal gene expression gradients enriched for developmental processes.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"3396-3411.e6"},"PeriodicalIF":14.7,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11502256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS. 核斑点完整性的破坏使 C9ORF72-FTD/ALS 中的 RNA 剪接失调。

IF 14.7 1区医学

Neuron Pub Date : 2024-10-23 Epub Date: 2024-08-23 DOI: 10.1016/j.neuron.2024.07.025

Rong Wu, Yingzhi Ye, Daoyuan Dong, Zhe Zhang, Shaopeng Wang, Yini Li, Noelle Wright, Javier Redding-Ochoa, Koping Chang, Shaohai Xu, Xueting Tu, Chengzhang Zhu, Lyle W Ostrow, Xavier Roca, Juan C Troncoso, Bin Wu, Shuying Sun

{"title":"Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS.","authors":"Rong Wu, Yingzhi Ye, Daoyuan Dong, Zhe Zhang, Shaopeng Wang, Yini Li, Noelle Wright, Javier Redding-Ochoa, Koping Chang, Shaohai Xu, Xueting Tu, Chengzhang Zhu, Lyle W Ostrow, Xavier Roca, Juan C Troncoso, Bin Wu, Shuying Sun","doi":"10.1016/j.neuron.2024.07.025","DOIUrl":"10.1016/j.neuron.2024.07.025","url":null,"abstract":"Expansion of an intronic (GGGGCC)n repeat within the C9ORF72 gene is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (C9-FTD/ALS), characterized with aberrant repeat RNA foci and noncanonical translation-produced dipeptide repeat (DPR) protein inclusions. Here, we elucidate that the (GGGGCC)n repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics. Moreover, the essential nuclear speckle scaffold protein SRRM2 is sequestered into the poly-GR cytoplasmic inclusions in the C9-FTD/ALS mouse model and patient postmortem tissues, exacerbating the nuclear speckle dysfunction. Impaired nuclear speckle integrity induces global exon skipping and intron retention in human iPSC-derived neurons and causes neuronal toxicity. Similar alternative splicing changes can be found in C9-FTD/ALS patient postmortem tissues. This work identified novel molecular mechanisms of global RNA splicing defects caused by impaired nuclear speckle function in C9-FTD/ALS and revealed novel potential biomarkers or therapeutic targets.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"3434-3451.e11"},"PeriodicalIF":14.7,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11502262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Insights into mechanisms and therapeutic avenues for primary familial brain calcification. 原发性家族性脑部钙化的机制和治疗途径透视。

IF 14.7 1区医学

Neuron Pub Date : 2024-10-09 DOI: 10.1016/j.neuron.2024.09.019

Christer Betsholtz

引用次数: 0

Structural basis of psychedelic LSD recognition at dopamine D₁ receptor. 多巴胺 D1 受体识别迷幻剂 LSD 的结构基础。

IF 14.7 1区医学

Neuron Pub Date : 2024-10-09 Epub Date: 2024-08-01 DOI: 10.1016/j.neuron.2024.07.003

Luyu Fan, Youwen Zhuang, Hongyu Wu, Huiqiong Li, Youwei Xu, Yue Wang, Licong He, Shishan Wang, Zhangcheng Chen, Jianjun Cheng, H Eric Xu, Sheng Wang

{"title":"Structural basis of psychedelic LSD recognition at dopamine D1 receptor.","authors":"Luyu Fan, Youwen Zhuang, Hongyu Wu, Huiqiong Li, Youwei Xu, Yue Wang, Licong He, Shishan Wang, Zhangcheng Chen, Jianjun Cheng, H Eric Xu, Sheng Wang","doi":"10.1016/j.neuron.2024.07.003","DOIUrl":"10.1016/j.neuron.2024.07.003","url":null,"abstract":"Understanding the kinetics of LSD in receptors and subsequent induced signaling is crucial for comprehending both the psychoactive and therapeutic effects of LSD. Despite extensive research on LSD's interactions with serotonin 2A and 2B receptors, its behavior on other targets, including dopamine receptors, has remained elusive. Here, we present cryo-EM structures of LSD/PF6142-bound dopamine D1 receptor (DRD1)-legobody complexes, accompanied by a β-arrestin-mimicking nanobody, NBA3, shedding light on the determinants of G protein coupling versus β-arrestin coupling. Structural analysis unveils a distinctive binding mode of LSD in DRD1, particularly with the ergoline moiety oriented toward TM4. Kinetic investigations uncover an exceptionally rapid dissociation rate of LSD in DRD1, attributed to the flexibility of extracellular loop 2 (ECL2). Moreover, G protein can stabilize ECL2 conformation, leading to a significant slowdown in ligand's dissociation rate. These findings establish a solid foundation for further exploration of G protein-coupled receptor (GPCR) dynamics and their relevance to signal transduction.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"3295-3310.e8"},"PeriodicalIF":14.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Feedback needs experience. 反馈需要经验。

IF 14.7 1区医学

Neuron Pub Date : 2024-10-09 DOI: 10.1016/j.neuron.2024.09.016

Leon Kremers, Tobias Rose

引用次数: 0

Ketamine alleviates NMDA receptor hypofunction through synaptic trapping. 氯胺酮通过突触诱捕缓解 NMDA 受体功能减退。

IF 14.7 1区医学

Neuron Pub Date : 2024-10-09 Epub Date: 2024-07-23 DOI: 10.1016/j.neuron.2024.06.028

Frédéric Villéga, Alexandra Fernandes, Julie Jézéquel, Floriane Uyttersprot, Nathan Benac, Sarra Zenagui, Laurine Bastardo, Hélène Gréa, Delphine Bouchet, Léa Villetelle, Olivier Nicole, Véronique Rogemond, Jérôme Honnorat, Julien P Dupuis, Laurent Groc

{"title":"Ketamine alleviates NMDA receptor hypofunction through synaptic trapping.","authors":"Frédéric Villéga, Alexandra Fernandes, Julie Jézéquel, Floriane Uyttersprot, Nathan Benac, Sarra Zenagui, Laurine Bastardo, Hélène Gréa, Delphine Bouchet, Léa Villetelle, Olivier Nicole, Véronique Rogemond, Jérôme Honnorat, Julien P Dupuis, Laurent Groc","doi":"10.1016/j.neuron.2024.06.028","DOIUrl":"10.1016/j.neuron.2024.06.028","url":null,"abstract":"Activity-dependent modulations of N-methyl-D-aspartate glutamate receptor (NMDAR) trapping at synapses regulate excitatory neurotransmission and shape cognitive functions. Although NMDAR synaptic destabilization has been associated with severe neurological and psychiatric conditions, tuning NMDAR synaptic trapping to assess its clinical relevance for the treatment of brain conditions remains a challenge. Here, we report that ketamine (KET) and other clinically relevant NMDAR open channel blockers (OCBs) promote interactions between NMDAR and PDZ-domain-containing scaffolding proteins and enhance NMDAR trapping at synapses. We further show that KET-elicited trapping enhancement compensates for depletion in synaptic receptors triggered by autoantibodies from patients with anti-NMDAR encephalitis. Preventing synaptic depletion mitigates impairments in NMDAR-mediated CaMKII signaling and alleviates anxiety- and sensorimotor-gating-related behavioral deficits provoked by autoantibodies. Altogether, these findings reveal an unexpected dimension of OCB action and stress the potential of targeting receptor anchoring in NMDAR-related synaptopathies.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"3311-3328.e9"},"PeriodicalIF":14.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Coding of self and environment by Pacinian neurons in freely moving animals. 自由运动动物的帕氏神经元对自我和环境的编码

IF 14.7 1区医学

Neuron Pub Date : 2024-10-09 Epub Date: 2024-08-07 DOI: 10.1016/j.neuron.2024.07.008

Josef Turecek, David D Ginty

引用次数: 0

Transformation of neural coding for vibrotactile stimuli along the ascending somatosensory pathway. 振动触觉刺激神经编码沿着体感上升通路的转变。

IF 14.7 1区医学

Neuron Pub Date : 2024-10-09 Epub Date: 2024-08-06 DOI: 10.1016/j.neuron.2024.07.005

Kuo-Sheng Lee, Alastair J Loutit, Dominica de Thomas Wagner, Mark Sanders, Mario Prsa, Daniel Huber

{"title":"Transformation of neural coding for vibrotactile stimuli along the ascending somatosensory pathway.","authors":"Kuo-Sheng Lee, Alastair J Loutit, Dominica de Thomas Wagner, Mark Sanders, Mario Prsa, Daniel Huber","doi":"10.1016/j.neuron.2024.07.005","DOIUrl":"10.1016/j.neuron.2024.07.005","url":null,"abstract":"In mammals, action potentials fired by rapidly adapting mechanosensitive afferents are known to reliably time lock to the cycles of a vibration. How and where along the ascending neuraxis is the peripheral afferent temporal code transformed into a rate code are currently not clear. Here, we probed the encoding of vibrotactile stimuli with electrophysiological recordings along major stages of the ascending somatosensory pathway in mice. We discovered the main transformation step was identified at the level of the thalamus, and parvalbumin-positive interneurons in thalamic reticular nucleus participate in sharpening frequency selectivity and in disrupting the precise spike timing. When frequency-specific microstimulation was applied within the brainstem, it generated frequency selectivity reminiscent of real vibration responses in the somatosensory cortex and could provide informative and robust signals for learning in behaving mice. Taken together, these findings could guide biomimetic stimulus strategies to activate specific nuclei along the ascending somatosensory pathway for neural prostheses.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"3343-3353.e7"},"PeriodicalIF":14.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antisense oligonucleotides enhance SLC20A2 expression and suppress brain calcification in a humanized mouse model. 在人源化小鼠模型中，反义寡核苷酸可增强 SLC20A2 的表达并抑制脑钙化。

IF 14.7 1区医学

Neuron Pub Date : 2024-10-09 Epub Date: 2024-08-08 DOI: 10.1016/j.neuron.2024.07.013

Miao Zhao, Xuewen Cheng, Lei Chen, Yi-Heng Zeng, Kai-Jun Lin, Yun-Lu Li, Ze-Hong Zheng, Xue-Jing Huang, Dan-Dan Zuo, Xin-Xin Guo, Jun Guo, Dian He, Ying Liu, Yu Lin, Chong Wang, Wen-Qi Lv, Hui-Zhen Su, Xiang-Ping Yao, Zi-Ling Ye, Xiao-Hong Chen, Ying-Qian Lu, Chen-Wei Huang, Guang Yang, Yu-Xian Zhang, Min-Ting Lin, Ning Wang, Zhi-Qi Xiong, Wan-Jin Chen

{"title":"Antisense oligonucleotides enhance SLC20A2 expression and suppress brain calcification in a humanized mouse model.","authors":"Miao Zhao, Xuewen Cheng, Lei Chen, Yi-Heng Zeng, Kai-Jun Lin, Yun-Lu Li, Ze-Hong Zheng, Xue-Jing Huang, Dan-Dan Zuo, Xin-Xin Guo, Jun Guo, Dian He, Ying Liu, Yu Lin, Chong Wang, Wen-Qi Lv, Hui-Zhen Su, Xiang-Ping Yao, Zi-Ling Ye, Xiao-Hong Chen, Ying-Qian Lu, Chen-Wei Huang, Guang Yang, Yu-Xian Zhang, Min-Ting Lin, Ning Wang, Zhi-Qi Xiong, Wan-Jin Chen","doi":"10.1016/j.neuron.2024.07.013","DOIUrl":"10.1016/j.neuron.2024.07.013","url":null,"abstract":"Primary familial brain calcification (PFBC) is a genetic neurological disease, yet no effective treatment is currently available. Here, we identified five novel intronic variants in SLC20A2 gene from six PFBC families. Three of these variants increased aberrant SLC20A2 pre-mRNA splicing by altering the binding affinity of splicing machineries to newly characterized cryptic exons, ultimately causing premature termination of SLC20A2 translation. Inhibiting the cryptic-exon incorporation with splice-switching ASOs increased the expression levels of functional SLC20A2 in cells carrying SLC20A2 mutations. Moreover, by knocking in a humanized SLC20A2 intron 2 sequence carrying a PFBC-associated intronic variant, the SLC20A2-KI mice exhibited increased inorganic phosphate (Pi) levels in cerebrospinal fluid (CSF) and progressive brain calcification. Intracerebroventricular administration of ASOs to these SLC20A2-KI mice reduced CSF Pi levels and suppressed brain calcification. Together, our findings expand the genetic etiology of PFBC and demonstrate ASO-mediated splice modulation as a potential therapy for PFBC patients with SLC20A2 haploinsufficiency.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"3278-3294.e7"},"PeriodicalIF":14.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Holistic inside and outside: The impact of food taste on ARC^AGRP neuron activity in feeding regulation. 内外兼修：食物味道对进食调节中 ARCAGRP 神经元活动的影响。

IF 14.7 1区医学

Neuron Pub Date : 2024-10-09 DOI: 10.1016/j.neuron.2024.09.011

Xiao Yang, Weijie Yan, Rong Gong

引用次数: 0

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