ADF/Cofilin Controls Synaptic Actin Dynamics and Regulates Synaptic Vesicle Mobilization and Exocytosis.
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.
Department of Biology, Neurobiology/Neurophysiology Group, University of Kaiserslautern, Kaiserslautern 67663, Germany.
Michael
M
Wolf
Department of Biology, Neurobiology/Neurophysiology Group, University of Kaiserslautern, Kaiserslautern 67663, Germany.
Anika-Maria
AM
Zimmermann
Department of Biology, Neurobiology/Neurophysiology Group, University of Kaiserslautern, Kaiserslautern 67663, Germany Current address: Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Andreas
A
Görlich
Institute of Genetics, University of Bonn, Bonn 53115, Germany.
Christine B
CB
Gurniak
Department of Anatomy, Pharmacology and Forensic Medicine and National Institute of Neuroscience-Italy, University of Turin, Turin 10126, Italy.
Marco
M
Sassoè-Pognetto
Animal Physiology Group, University of Kaiserslautern, Kaiserslautern 67663, Germany.
Eckhard
E
Friauf
Institute of Genetics, University of Bonn, Bonn 53115, Germany.
Walter
W
Witke
Department of Biology, Neurobiology/Neurophysiology Group, University of Kaiserslautern, Kaiserslautern 67663, Germany Institute of Physiological Chemistry, University of Marburg, 35043 Marburg, Germany.
Marco B
MB
Rust
D000199:Actins / Q000378:metabolism*; D000818:Animals; D051338:Cofilin 1 / Q000235:genetics / Q000378:metabolism*; D051345:Destrin / Q000235:genetics / Q000378:metabolism*; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D005089:Exocytosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D010766:Phosphorylation; D011189:Potassium Chloride / Q000494:pharmacology; D016548:Prosencephalon / Q000166:cytology; D021381:Protein Transport / Q000235:genetics / Q000502:physiology*; D050600:SNARE Proteins / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D013572:Synaptic Vesicles / Q000378:metabolism*
D000199:Actins; D051338:Cofilin 1; D051345:Destrin; C495825:Dstn protein, mouse; D050600:SNARE Proteins; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D011189:Potassium Chloride
CA3–CA1 synapse; hippocampus; neurotransmitter release; presynaptic physiology; synaptic plasticity