Pub Date : 2026-02-04DOI: 10.1016/j.neuron.2025.12.004
Agata Nowacka, Angela M Getz, Hanna L Zieger, Maxime Malivert, Diogo Bessa-Neto, Elisabete Augusto, Christelle Breillat, Sophie Daburon, Cécile Lemoigne, Sébastien Marais, Mathieu Ducros, Alexandre Favereaux, Andrew C Penn, Richard Naud, Matthieu Sainlos, Daniel Choquet
Synaptic responses adapt on millisecond-to-second timescales through short-term plasticity (STP), a key process that filters and transforms neuronal information. While STP is classically ascribed to presynaptic release mechanisms, postsynaptic receptor properties-particularly desensitization and surface diffusion-also shape synaptic responses. Here, we dissect pre- and postsynaptic contributions to synaptic adaptation using molecular tools to visualize glutamate release and manipulate AMPA receptor (AMPAR) diffusion in intact circuits. We find that synaptic gain during STP is tuned by synapse-specific regulation of AMPAR biophysics and diffusion-trapping. These features are determined constitutively by auxiliary subunit profiles and dynamically by activity-dependent signaling engaged during long-term plasticity. With modeling, we quantified how short-term synaptic dynamics are impacted by postsynaptic regulation of filtering properties, which broadened heterogeneity of filtering timescales to refine temporal selectivity in synaptic networks. By augmenting desensitization-mediated synaptic depression, AMPAR diffusion-trapping emerges as a fundamental regulatory mechanism of postsynaptic integration and circuit-level information processing.
{"title":"Synapse-specific and plasticity-regulated AMPA receptor mobility tunes synaptic integration.","authors":"Agata Nowacka, Angela M Getz, Hanna L Zieger, Maxime Malivert, Diogo Bessa-Neto, Elisabete Augusto, Christelle Breillat, Sophie Daburon, Cécile Lemoigne, Sébastien Marais, Mathieu Ducros, Alexandre Favereaux, Andrew C Penn, Richard Naud, Matthieu Sainlos, Daniel Choquet","doi":"10.1016/j.neuron.2025.12.004","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.12.004","url":null,"abstract":"<p><p>Synaptic responses adapt on millisecond-to-second timescales through short-term plasticity (STP), a key process that filters and transforms neuronal information. While STP is classically ascribed to presynaptic release mechanisms, postsynaptic receptor properties-particularly desensitization and surface diffusion-also shape synaptic responses. Here, we dissect pre- and postsynaptic contributions to synaptic adaptation using molecular tools to visualize glutamate release and manipulate AMPA receptor (AMPAR) diffusion in intact circuits. We find that synaptic gain during STP is tuned by synapse-specific regulation of AMPAR biophysics and diffusion-trapping. These features are determined constitutively by auxiliary subunit profiles and dynamically by activity-dependent signaling engaged during long-term plasticity. With modeling, we quantified how short-term synaptic dynamics are impacted by postsynaptic regulation of filtering properties, which broadened heterogeneity of filtering timescales to refine temporal selectivity in synaptic networks. By augmenting desensitization-mediated synaptic depression, AMPAR diffusion-trapping emerges as a fundamental regulatory mechanism of postsynaptic integration and circuit-level information processing.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125957","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}
Pub Date : 2026-02-04DOI: 10.1016/j.neuron.2025.12.005
Honghe Liu, Mingming Liu, Yang Liu, Gege Gui, Tapas Paul, Yu-Ning Lu, Zhiyuan Huang, Haocheng Wang, Yatao Xiao, Zhongfan Zheng, Goran Periz, Yingxiao Shi, Justin K Ichida, Sua Myong, Hongkai Ji, Jiou Wang
A hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. While repeat RNAs are implicated in disease pathogenesis, their mechanisms of action remain incompletely understood. Here, we show that GGGGCC repeat RNA engages chromatin genome-wide preferentially at promoter regions in patient cells. This interaction obstructs RNA polymerase II and transcription factors with GC-rich motifs, leading to broad transcriptional repression. Biochemical assays, single-molecule imaging, and native bisulfite sequencing analyses demonstrate that GGGGCC repeat RNA intrinsically forms DNA:RNA hybrid G-quadruplexes (HQs) with cognate DNA, providing a structural basis for transcriptional interference. Stabilization of these G-quadruplex structures exacerbates neuronal vulnerability to metabolic stress in patient-derived motor neurons and cortical organoids, whereas restoring key gene dysregulation improves resistance. These findings uncover a previously unrecognized trans-acting mechanism whereby repetitive RNAs form hybrid structures with genomic DNA, disrupt gene regulation, and contribute to neurodegeneration.
{"title":"C9orf72 hexanucleotide repeat RNA drives transcriptional dysregulation through genome-wide DNA:RNA hybrid G-quadruplexes.","authors":"Honghe Liu, Mingming Liu, Yang Liu, Gege Gui, Tapas Paul, Yu-Ning Lu, Zhiyuan Huang, Haocheng Wang, Yatao Xiao, Zhongfan Zheng, Goran Periz, Yingxiao Shi, Justin K Ichida, Sua Myong, Hongkai Ji, Jiou Wang","doi":"10.1016/j.neuron.2025.12.005","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.12.005","url":null,"abstract":"<p><p>A hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. While repeat RNAs are implicated in disease pathogenesis, their mechanisms of action remain incompletely understood. Here, we show that GGGGCC repeat RNA engages chromatin genome-wide preferentially at promoter regions in patient cells. This interaction obstructs RNA polymerase II and transcription factors with GC-rich motifs, leading to broad transcriptional repression. Biochemical assays, single-molecule imaging, and native bisulfite sequencing analyses demonstrate that GGGGCC repeat RNA intrinsically forms DNA:RNA hybrid G-quadruplexes (HQs) with cognate DNA, providing a structural basis for transcriptional interference. Stabilization of these G-quadruplex structures exacerbates neuronal vulnerability to metabolic stress in patient-derived motor neurons and cortical organoids, whereas restoring key gene dysregulation improves resistance. These findings uncover a previously unrecognized trans-acting mechanism whereby repetitive RNAs form hybrid structures with genomic DNA, disrupt gene regulation, and contribute to neurodegeneration.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125889","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}
Pub Date : 2026-02-03DOI: 10.1016/j.neuron.2025.12.037
Rachael E. Hokenson, Kiara L. Rodríguez-Acevedo, Yuncai Chen, Annabel K. Short, Sara A. Samrari, Brinda Devireddy, Brittany J. Jensen, Julia J. Winter, Christine M. Gall, Kiran K. Soma, Elizabeth A. Heller, Tallie Z. Baram
{"title":"Hippocampal estrogen levels, receptor types, and epigenetics contribute to sex-specific memory vulnerabilities to concurrent acute stresses","authors":"Rachael E. Hokenson, Kiara L. Rodríguez-Acevedo, Yuncai Chen, Annabel K. Short, Sara A. Samrari, Brinda Devireddy, Brittany J. Jensen, Julia J. Winter, Christine M. Gall, Kiran K. Soma, Elizabeth A. Heller, Tallie Z. Baram","doi":"10.1016/j.neuron.2025.12.037","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.12.037","url":null,"abstract":"","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"89 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146110559","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}
Pub Date : 2026-02-03DOI: 10.1016/j.neuron.2025.12.031
Shiqiang Hu, Jianfan Yang, Siqi Yin, Yijie Zhong, Yanzun An, Yuyang Guo, Zihan Zhai, Yi Zhong
{"title":"Identification of an engram ensemble mediating memory forgetting in the dentate gyrus","authors":"Shiqiang Hu, Jianfan Yang, Siqi Yin, Yijie Zhong, Yanzun An, Yuyang Guo, Zihan Zhai, Yi Zhong","doi":"10.1016/j.neuron.2025.12.031","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.12.031","url":null,"abstract":"","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"16 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146110556","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}
Pub Date : 2026-01-30DOI: 10.1016/j.neuron.2025.11.018
Heather Leduc-Pessah, Brendan B. McAllister, Sarthak Sinha, Sierra Stokes-Heck, Daisuke Nishizawa, Churmy Y. Fan, Marie-Kim St-Pierre, Amyaouch Bradaia, Manon Defaye, Nicole E. Burma, Jonathan Damblon, Einer Muñoz-Pino, Frank Visser, Marie-France Dorion, Luke M. Healy, Ye Man Tang, Julia Canet-Pons, Nynke J. van den Hoogen, Zizhen Zhang, Flavia T.T. Antunes, Valerio E.C. Piscopo, Margaret Medina, Ken-ichi Fukuda, Tatsuya Ichinohe, Makoto Nagashima, Masakazu Hayashida, Emma Johnson, Arpana Agrawal, Louisa Degenhardt, Nicholas G. Martin, Gerald W. Zamponi, Elliot C. Nelson, Christophe Altier, Marie-Eve Tremblay, Chad Bousman, Stefano Stifani, Yves De Koninck, Kazutaka Ikeda, Jeff Biernaskie, Tuan Trang
{"title":"Runx1 transcription factor modulates opioid analgesia and withdrawal in humans and rodents","authors":"Heather Leduc-Pessah, Brendan B. McAllister, Sarthak Sinha, Sierra Stokes-Heck, Daisuke Nishizawa, Churmy Y. Fan, Marie-Kim St-Pierre, Amyaouch Bradaia, Manon Defaye, Nicole E. Burma, Jonathan Damblon, Einer Muñoz-Pino, Frank Visser, Marie-France Dorion, Luke M. Healy, Ye Man Tang, Julia Canet-Pons, Nynke J. van den Hoogen, Zizhen Zhang, Flavia T.T. Antunes, Valerio E.C. Piscopo, Margaret Medina, Ken-ichi Fukuda, Tatsuya Ichinohe, Makoto Nagashima, Masakazu Hayashida, Emma Johnson, Arpana Agrawal, Louisa Degenhardt, Nicholas G. Martin, Gerald W. Zamponi, Elliot C. Nelson, Christophe Altier, Marie-Eve Tremblay, Chad Bousman, Stefano Stifani, Yves De Koninck, Kazutaka Ikeda, Jeff Biernaskie, Tuan Trang","doi":"10.1016/j.neuron.2025.11.018","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.11.018","url":null,"abstract":"","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"29 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089268","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}
Pub Date : 2026-01-28DOI: 10.1016/j.neuron.2025.11.021
Caleb Weinreb, Lakshanyaa Thamarai Kannan, Alia Newman-Boulle, Tim Sainburg, Winthrop F. Gillis, Alex Plotnikoff, Sofia Makowska, Jonah E. Pearl, Mohammed Abdal Monium Osman, Scott W. Linderman, Sandeep Robert Datta
{"title":"Spontaneous behavior is a succession of self-directed tasks","authors":"Caleb Weinreb, Lakshanyaa Thamarai Kannan, Alia Newman-Boulle, Tim Sainburg, Winthrop F. Gillis, Alex Plotnikoff, Sofia Makowska, Jonah E. Pearl, Mohammed Abdal Monium Osman, Scott W. Linderman, Sandeep Robert Datta","doi":"10.1016/j.neuron.2025.11.021","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.11.021","url":null,"abstract":"","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"8 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146072082","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}
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