ADF/Cofilin Controls Synaptic Actin Dynamics and Regulates Synaptic Vesicle Mobilization and Exocytosis

• Published in: Cerebral cortex (New York, N.Y. 1991) N.Y. 1991), 2015-09, Vol.25 (9), p.2863-2875
• Main Authors: Wolf, Michael, Zimmermann, Anika-Maria, Görlich, Andreas, Gurniak, Christine B, Sassoè-Pognetto, Marco, Friauf, Eckhard, Witke, Walter, Rust, Marco B
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Animals; Cofilin 1 - genetics; Cofilin 1 - metabolism; Destrin - genetics; Destrin - metabolism; Electric Stimulation; Excitatory Postsynaptic Potentials - genetics; Excitatory Postsynaptic Potentials - physiology; Exocytosis - drug effects; Exocytosis - genetics; Exocytosis - physiology; Glutamic Acid - metabolism; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Mice; Mice, Transgenic; Mutation - genetics; Neurons - drug effects; Neurons - physiology; Neurons - ultrastructure; Phosphorylation; Potassium Chloride - pharmacology; Prosencephalon - cytology; Protein Transport - genetics; Protein Transport - physiology; SNARE Proteins - metabolism; Synapses - drug effects; Synapses - physiology; Synapses - ultrastructure; Synaptic Vesicles - metabolism
• ISSN: 1047-3211; 1460-2199
• DOI: 10.1093/cercor/bhu081

Actin is a regulator of synaptic vesicle mobilization and exocytosis, but little is known about the mechanisms that regulate actin at presynaptic terminals. Genetic data on LIMK1, a negative regulator of actin-depolymerizing proteins of the ADF/cofilin family, suggest a role for ADF/cofilin in presynaptic function. However, synapse physiology is fully preserved upon genetic ablation of ADF in mice, and n-cofilin mutant mice display defects in postsynaptic plasticity, but not in presynaptic function. One explanation for this phenomenon is overlapping functions of ADF and n-cofilin in presynaptic physiology. Here, we tested this hypothesis and genetically removed ADF together with n-cofilin from synapses. In double mutants for ADF and n-cofilin, synaptic actin dynamics was impaired and more severely affected than in single mutants. The resulting cytoskeletal defects heavily affected the organization, mobilization, and exocytosis of synaptic vesicles in hippocampal CA3-CA1 synapses. Our data for the first time identify overlapping functions for ADF and n-cofilin in presynaptic physiology and vesicle trafficking. We conclude that n-cofilin is a limiting factor in postsynaptic plasticity, a function which cannot be substituted by ADF. On the presynaptic side, the presence of either ADF or n-cofilin is sufficient to control actin remodeling during vesicle release.