@article{5293ce1b092547c48daa52a5fefdf420,
title = "Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome",
abstract = "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.",
keywords = "CP: Developmental biology, CP: Neuroscience, LC-MS/MS, ankyrin, anti-epileptic drug, calcium imaging, postsynaptic interactome, proteomics, synchrony",
author = "Sehyoun Yoon and Santos, {Marc Dos} and Forrest, {Marc P.} and Pratt, {Christopher P.} and Natalia Khalatyan and Mohler, {Peter J.} and Savas, {Jeffrey N.} and Peter Penzes",
note = "Funding Information: This work was supported by R01MH107182 to P.P. and an Individual Biomedical Research Award from The Hartwell Foundation (J.N.S). This work was supported by Northwestern University's Center for Advanced Microscopy and a Cancer Center Support Grant (NCI CA060553 ), as well as the Northwestern University Behavioral Phenotyping Core . Graphical abstract, Figure 3A, and Figure 4A were created with Biorender.com ( https://biorender.com/ ). Funding Information: This work was supported by R01MH107182 to P.P. and an Individual Biomedical Research Award from The Hartwell Foundation (J.N.S). This work was supported by Northwestern University's Center for Advanced Microscopy and a Cancer Center Support Grant (NCI CA060553), as well as the Northwestern University Behavioral Phenotyping Core. Graphical abstract, Figure 3A, and Figure 4A were created with Biorender.com (https://biorender.com/). The authors are from the Department of Neuroscience (S.Y. M.S. M.F. C.P. P.P.), Department of Psychiatry and Behavioral Sciences (P.P.), and Department of Neurology (N.K. J.S.), Northwestern University Feinberg School of Medicine, Chicago, Illinois. S.Y. initiated the project, and S.Y. and M.S. performed all experiments and data analysis unless otherwise stated. C.P. produced Ank2−/−:NEX-Cre and Ank2+/−:NEX-Cre mice and checked the mortality. N.K. and J.S. performed 10 plex TMT LC-MS3 and IP LC-MS/MS. M.F. helped analyze the 10 plex TMT LC-MS3 multinotch data. P.M. designed and backcrossed the animal model. P.P. supervised the project and interpreted data. The authors declare that they have no conflict of interest. Publisher Copyright: {\textcopyright} 2023",
year = "2023",
month = jul,
day = "25",
doi = "10.1016/j.celrep.2023.112784",
language = "English (US)",
volume = "42",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}