Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome
Summary: Rare genetic variants in ANK2, which encodes ankyrin-B, are associated with neurodevelopmental disorders (NDDs); however, their pathogenesis is poorly understood. We find that mice with prenatal deletion in cortical excitatory neurons and oligodendrocytes (Ank2−/−:Emx1-Cre), but not with ad...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723007957 |
| _version_ | 1827904466753421312 |
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| author | Sehyoun Yoon Marc Dos Santos Marc P. Forrest Christopher P. Pratt Natalia Khalatyan Peter J. Mohler Jeffrey N. Savas Peter Penzes |
| author_facet | Sehyoun Yoon Marc Dos Santos Marc P. Forrest Christopher P. Pratt Natalia Khalatyan Peter J. Mohler Jeffrey N. Savas Peter Penzes |
| author_sort | Sehyoun Yoon |
| collection | DOAJ |
| description | Summary: Rare genetic variants in ANK2, which encodes ankyrin-B, are associated with neurodevelopmental disorders (NDDs); however, their pathogenesis is poorly understood. We find that mice with prenatal deletion in cortical excitatory neurons and oligodendrocytes (Ank2−/−:Emx1-Cre), but not with adolescent deletion in forebrain excitatory neurons (Ank2−/−:CaMKIIα-Cre), display severe spontaneous seizures, increased mortality, hyperactivity, and social deficits. Calcium imaging of cortical slices from Ank2−/−:Emx1-Cre mice shows increased neuronal calcium event amplitude and frequency, along with network hyperexcitability and hypersynchrony. Quantitative proteomic analysis of cortical synaptic membranes reveals upregulation of dendritic spine plasticity-regulatory proteins and downregulation of intermediate filaments. Characterization of the ankyrin-B interactome identifies interactors associated with autism and epilepsy risk factors and synaptic proteins. The AMPA receptor antagonist, perampanel, restores cortical neuronal activity and partially rescues survival in Ank2−/−:Emx1-Cre mice. Our findings suggest that synaptic proteome alterations resulting from Ank2 deletion impair neuronal activity and synchrony, leading to NDDs-related behavioral impairments. |
| first_indexed | 2024-03-13T00:27:52Z |
| format | Article |
| id | doaj.art-2e405b575a864345a6945ca6fb17a8ae |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-13T00:27:52Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-2e405b575a864345a6945ca6fb17a8ae2023-07-11T04:06:21ZengElsevierCell Reports2211-12472023-07-01427112784Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteomeSehyoun Yoon0Marc Dos Santos1Marc P. Forrest2Christopher P. Pratt3Natalia Khalatyan4Peter J. Mohler5Jeffrey N. Savas6Peter Penzes7Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartment of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartment of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartment of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartment of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartments of Internal Medicine and Physiology, Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia Research; Ohio State University College of Medicine, Columbus, OH 43210, USADepartment of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartment of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Northwestern University, Center for Autism and Neurodevelopment, Chicago, IL 60611, USA; Corresponding authorSummary: Rare genetic variants in ANK2, which encodes ankyrin-B, are associated with neurodevelopmental disorders (NDDs); however, their pathogenesis is poorly understood. We find that mice with prenatal deletion in cortical excitatory neurons and oligodendrocytes (Ank2−/−:Emx1-Cre), but not with adolescent deletion in forebrain excitatory neurons (Ank2−/−:CaMKIIα-Cre), display severe spontaneous seizures, increased mortality, hyperactivity, and social deficits. Calcium imaging of cortical slices from Ank2−/−:Emx1-Cre mice shows increased neuronal calcium event amplitude and frequency, along with network hyperexcitability and hypersynchrony. Quantitative proteomic analysis of cortical synaptic membranes reveals upregulation of dendritic spine plasticity-regulatory proteins and downregulation of intermediate filaments. Characterization of the ankyrin-B interactome identifies interactors associated with autism and epilepsy risk factors and synaptic proteins. The AMPA receptor antagonist, perampanel, restores cortical neuronal activity and partially rescues survival in Ank2−/−:Emx1-Cre mice. Our findings suggest that synaptic proteome alterations resulting from Ank2 deletion impair neuronal activity and synchrony, leading to NDDs-related behavioral impairments.http://www.sciencedirect.com/science/article/pii/S2211124723007957CP: NeuroscienceCP: Developmental biology |
| spellingShingle | Sehyoun Yoon Marc Dos Santos Marc P. Forrest Christopher P. Pratt Natalia Khalatyan Peter J. Mohler Jeffrey N. Savas Peter Penzes Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome Cell Reports CP: Neuroscience CP: Developmental biology |
| title | Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome |
| title_full | Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome |
| title_fullStr | Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome |
| title_full_unstemmed | Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome |
| title_short | Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome |
| title_sort | early developmental deletion of forebrain ank2 causes seizure related phenotypes by reshaping the synaptic proteome |
| topic | CP: Neuroscience CP: Developmental biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723007957 |
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