Angelman syndrome (AS) is a neurogenetic disorder characterized by motor coordination and cognitive deficits. In AS, hippocampal neurons show reduced filamentous 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 filamentous 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. Significance Statement Angelman syndrome (AS) is a severe neurogenetic disorder characterized by significant motor and cognitive impairments; however, effective treatments remain elusive. Recent evidence implicates deficits in the mechanosensitive PIEZO2 channel and AMPA receptor function, as well as cytoskeletal abnormalities in AS pathology. Our study identifies cofilin, an actin-binding protein, as a regulator of ion channel function. We demonstrate that pharmacological inhibition of cofilin restores PIEZO2 channel and AMPA receptor activities, enhances neuronal excitability, and improves motor coordination and learning in a mouse model of AS. These findings reveal a novel mechanism by which actin dynamics influence sensory and cognitive function.
Romero et al. (Thu,) studied this question.