Cofilin Inhibition Ameliorates PIEZO2 and AMPA Dysfunction in a Mouse Model of Angelman Syndrome

Authors

Luis O Romero
Manisha Bade
Elisa Carrillo
Sonia Paz-López
Syed A M Hasan
William James Antonisamy
Vasanthi Jayaraman
Zahoor A Shah
Valeria Vásquez
Julio F Cordero-Morales

Language

English

Publication Date

11-5-2025

Journal

The Journal of Neuroscience

DOI

10.1523/JNEUROSCI.0965-25.2025

PMID

41067919

PMCID

PMC12590110

PubMedCentral® Posted Date

10-9-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Angelman syndrome (AS) is a neurogenetic disorder characterized by motor coordination and cognitive deficits. In AS, hippocampal neurons show reduced filamentous (F-)actin, a decrease we also reported in dorsal root ganglia (DRG) neurons, along with impaired mechanosensitive ion channel activity. Currently, there are no pharmacological targets to prevent the decrease of F-actin in AS. Here, we utilize a first-in-class selective cofilin inhibitor (SZ-3) to restore PIEZO2 function in DRG neurons and glutamate-evoked currents in hippocampal neurons from AS mice. Using atomic force microscopy, we demonstrate that inhibiting cofilin, an actin-severing protein, with SZ-3 increases cellular stiffness by stabilizing the actin cytoskeleton. Furthermore, systemic administration of SZ-3 in male and female AS mice enhances their performance in the rotarod and T-maze tests. These findings support that cytoskeletal dysregulation contributes to impaired ion channel function and behavioral deficits and that actin-binding proteins could serve as a target for enhancing motor coordination and spatial learning in AS.

Keywords

Animals, Mice, Male, Female, Ion Channels, Disease Models, Animal, Angelman Syndrome, Receptors, AMPA, Hippocampus, Actin Depolymerizing Factors, Mice, Inbred C57BL, Ganglia, Spinal, Neurons, Maze Learning, Cells, Cultured, AMPA receptor, Angelman syndrome, cofilin, hippocampal neurons, PIEZO2, sensory neurons

Published Open-Access

yes

Recommended Citation

Romero, Luis O; Bade, Manisha; Carrillo, Elisa; et al., "Cofilin Inhibition Ameliorates PIEZO2 and AMPA Dysfunction in a Mouse Model of Angelman Syndrome" (2025). Faculty, Staff and Student Publications. 5490.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5490