ArticlebioRxiv : the preprint server for biology2025
An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes.
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71 authors.
Elisabetta FurlanisHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Min DaiHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Brenda Leyva GarciaHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Thien TranHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Josselyn VergaraHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Ana PereiraHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Bram L GorissenHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Sara WillsHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Anna VlachosEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Ariel HairstonHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Deepanjali DwivediHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Sarah DuHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Justin McMahonHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Shuhan HuangHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Annunziato MorabitoHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Arenski VazquezDominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York.
Soyoun KimDominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York.
Anthony T LeeDepartment of Neurological Surgery, University of California San Francisco, San Francisco, USA.
Edward F ChangDepartment of Neurological Surgery, University of California San Francisco, San Francisco, USA.
Taha RazzaqTibbling Technologies, Redmond, WA, USA.
Ahmed QaziTibbling Technologies, Redmond, WA, USA.
Geoffrey VargishEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Xiaoqing YuanEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Adam CaccavanoEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Steven HuntEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Ramesh ChittajalluEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Nadiya McLeanEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Lauren HewittEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Emily ParanzinoEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Haley RiceEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Alex C CumminsNational Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4415, USA.
Anya PlotnikovaNational Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4415, USA.
Arya MohantyNational Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4415, USA.
Anne Claire TangenNational Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4415, USA.
Jung Hoon ShinNational Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4415, USA.
Reza AzadiNational Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4415, USA.
Mark A G EldridgeNational Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4415, USA.
Veronica A AlvarezNational Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4415, USA.
Bruno B AverbeckNational Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4415, USA.
Mansour AlyahyayBiological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Kingdom of Saudi Arabia.
Tania Reyes VallejoBiological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Kingdom of Saudi Arabia.
Mohammed SoheibBiological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Kingdom of Saudi Arabia.
Lucas G VattinoEaton-Peabody Laboratories, Massachusetts Eye and Ear Infirmary Boston, USA.
Cathryn P MacGregorEaton-Peabody Laboratories, Massachusetts Eye and Ear Infirmary Boston, USA.
Carolina Piletti ChatainDepartment of Neuroscience, Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
Emmie BanksDepartment of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Viktor Janos OlahDepartment of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Shovan NaskarUnit of Functional Neural Circuit, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Sophie HillDepartment of Neuroscience, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Sophie LiebergallDepartment of Neuroscience, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Rohan BadianiHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Lili HydeHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Ella HanleyHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Qing XuBiological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Kingdom of Saudi Arabia.
Kathryn C AllawayHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Ethan M GoldbergDepartment of Neuroscience, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Matthew J M RowanDepartment of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Tomasz J NowakowskiDepartment of Neurological Surgery, University of California San Francisco, San Francisco, USA.
Soohyun LeeUnit of Functional Neural Circuit, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Emilia FavuzziDepartment of Neuroscience, Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
Pascal S KaeserHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Lucas SjulsonDominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York.
Renata Batista-BritoDominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York.
Anne E TakesianEaton-Peabody Laboratories, Massachusetts Eye and Ear Infirmary Boston, USA.
Leena A IbrahimBiological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Kingdom of Saudi Arabia.
Asim IqbalTibbling Technologies, Redmond, WA, USA.
Kenneth A PelkeyEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Chris J McBainEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Jordane DimidschsteinStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Gord FishellHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Yating WangHarvard Medical School, Blavatnik Institute, Department of Neurobiology, Boston, MA 02115, USA.
Funding
Systematic identification of enhancers to target the breadth of excitatory and inhibitory neuronal cell types in the cerebral cortexUF1MH130701 · NIMH · BROAD INSTITUTE, INC. · PI ARLOTTA, PAOLA, DEVERMAN, BENJAMIN E · 2022 to 2022
$10.7MDevelopment and validation of AAV vectors to manipulate specific neuronal subtypes and circuits involved in epilepsy and psychiatric disorders across mammalian species.UG3MH120096 · NIMH · BROAD INSTITUTE, INC. · PI DEVERMAN, BENJAMIN E, FISHELL, GORDON J · 2019 to 2021
$6.7MA cellular atlas of the primate and human basal gangliaU01MH124602 · NIMH · BROAD INSTITUTE, INC. · PI CHEN, FEI, FISHELL, GORDON J · 2021 to 2023
$5.0MDevelopment and validation of AAV vectors to manipulate specific neuronal subtypes and circuits involved in epilepsy and psychiatric disorders across mammalian species.UH3MH120096 · NIMH · BROAD INSTITUTE, INC. · PI DEVERMAN, BENJAMIN E, FISHELL, GORDON J · 2023 to 2024
$4.7MUC Irvine Center for the production and distribution of cell-type-specific viral targeting reagentsU24MH133236 · NIMH · UNIVERSITY OF CALIFORNIA-IRVINE · PI FISHELL, GORDON J, XU, XIANGMIN · 2023 to 2025
$3.6MSearching for the Goldilocks Zone of Innate Immunity in Alzheimer's DiseaseR01AG085557 · NIA · EMORY UNIVERSITY · PI Todd E Golde, Yona R Levites · 2024 to 2026
$3.0MAutomated cell-type-specific electrophysiology for understanding circuit dysregulation in Alzheimer's DiseaseRF1AG079269 · NIA · EMORY UNIVERSITY · PI FOREST, CRAIG, ROWAN, MATTHEW J.M. · 2022 to 2024
$2.4MAutomated cell-type-specific electrophysiology for understanding circuit dysregulation in Alzheimer's DiseaseR01AG079269 · NIA · EMORY UNIVERSITY · PI Craig Forest, Matthew J.M. Rowan · 2025 to 2026
$1.4MNIA NIH HHS R01 AG079269NIA NIH HHS R01 AG085557NIA NIH HHS RF1 AG079269NIMH NIH HHS U01 MH124602NIMH NIH HHS U24 MH133236NIMH NIH HHS UF1 MH130701NIMH NIH HHS UH3 MH120096
Abstract
In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate specific neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the telencephalic interneuron subtypes. We established a set of enhancer-AAV tools that are highly specific for distinct cortical interneuron populations and striatal cholinergic interneurons. These enhancers, when used in the context of different effectors, can target (fluorescent proteins), observe activity (GCaMP) and manipulate (opto-genetics) specific neuronal subtypes. We also validated our enhancer-AAV tools across species. Thus, we provide the field with a powerful set of tools to study neural circuits and functions and to develop precise and targeted therapy.
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