Romero, Luis O; Bade, Manisha; Carrillo, Elisa; Paz-López, Sonia; Hasan, Syed A M; Antonisamy, William Jame J; Jayaraman, Vasanthi; Shah, Zahoor A; Vásquez, Valeria; Cordero-Morales, Julio F
description
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.
