Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome
Sehyoun Yoon,
Marc Dos Santos,
Marc P. Forrest,
Christopher P. Pratt,
Natalia Khalatyan,
Peter J. Mohler,
Jeffrey N. Savas,
Peter Penzes
Affiliations
Sehyoun Yoon
Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Marc Dos Santos
Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Marc P. Forrest
Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Christopher P. Pratt
Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Natalia Khalatyan
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Peter J. Mohler
Departments 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, USA
Jeffrey N. Savas
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Peter Penzes
Department 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 author
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.
