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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number112784
JournalCell reports
Issue number7
StatePublished - Jul 25 2023


  • CP: Developmental biology
  • CP: Neuroscience
  • LC-MS/MS
  • ankyrin
  • anti-epileptic drug
  • calcium imaging
  • postsynaptic interactome
  • proteomics
  • synchrony

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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