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

Cereb Cortex. 2015 Sep;25(9):2863-75. doi: 10.1093/cercor/bhu081. Epub 2014 Apr 25.

Abstract

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.

Keywords: CA3–CA1 synapse; hippocampus; neurotransmitter release; presynaptic physiology; synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • Actins
  • Cofilin 1
  • Destrin
  • Dstn protein, mouse
  • SNARE Proteins
  • Green Fluorescent Proteins
  • Glutamic Acid
  • Potassium Chloride