| First Author | Yoon S | Year | 2023 |
| Journal | Cell Rep | Volume | 42 |
| Issue | 7 | Pages | 112784 |
| PubMed ID | 37428632 | Mgi Jnum | J:341060 |
| Mgi Id | MGI:7518131 | Doi | 10.1016/j.celrep.2023.112784 |
| Citation | Yoon S, et al. (2023) Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome. Cell Rep 42(7):112784 |
| abstractText | 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(-/-):CaMKIIalpha-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. |
