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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Bibliographic Details
Main Authors: Sehyoun Yoon, Marc Dos Santos, Marc P. Forrest, Christopher P. Pratt, Natalia Khalatyan, Peter J. Mohler, Jeffrey N. Savas, Peter Penzes
Format: Article
Language:English
Published: Elsevier 2023-07-01
Series:Cell Reports
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Online Access:http://www.sciencedirect.com/science/article/pii/S2211124723007957
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Summary: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.
ISSN:2211-1247