Attention-Deficit/Hyperactivity Disorder-like Phenotype in a Mouse Model with Impaired Actin Dynamics

Biol Psychiatry. 2015 Jul 15;78(2):95-106. doi: 10.1016/j.biopsych.2014.03.011. Epub 2014 Mar 21.


Background: Actin depolymerizing proteins of the actin depolymerizing factor (ADF)/cofilin family are essential for actin dynamics, which is critical for synaptic function. Two ADF/cofilin family members, ADF and n-cofilin, are highly abundant in the brain, where they are present in excitatory synapses. Previous studies demonstrated the relevance of n-cofilin for postsynaptic plasticity, associative learning, and anxiety. These studies also suggested overlapping functions for ADF and n-cofilin.

Methods: We performed pharmacobehavioral, electrophysiologic, and electron microscopic studies on ADF and n-cofilin single mutants and double mutants (named ACC mice) to characterize the importance of ADF/cofilin activity for synapse physiology and mouse behavior.

Results: The ACC mice, but not single mutants, exhibited hyperlocomotion, impulsivity, and impaired working memory. Hyperlocomotion and impulsive behavior were reversed by methylphenidate, a psychostimulant commonly used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Also, ACC mice displayed a disturbed morphology of striatal excitatory synapses, accompanied by strongly increased glutamate release. Blockade of dopamine or glutamate transmission resulted in normal locomotion.

Conclusions: Our study reveals that ADHD can result from a disturbed balance between excitation and inhibition in striatal circuits, providing novel insights into the mechanisms underlying this neurobehavioral disorder. Our results link actin dynamics to ADHD, suggesting that mutations in actin regulatory proteins may contribute to the etiology of ADHD in humans.

Keywords: ADF; ADHD; Actin dynamics; Hyperactivity; Locomotion; n-cofilin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Attention Deficit Disorder with Hyperactivity / genetics
  • Attention Deficit Disorder with Hyperactivity / physiopathology*
  • Attention Deficit Disorder with Hyperactivity / psychology*
  • Central Nervous System Stimulants / pharmacology
  • Cofilin 1 / genetics
  • Cofilin 1 / metabolism
  • Cofilin 1 / physiology*
  • Corpus Striatum / ultrastructure*
  • Destrin / genetics
  • Destrin / physiology*
  • Disease Models, Animal
  • Dopamine Antagonists
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
  • Excitatory Postsynaptic Potentials
  • Glutamates / metabolism
  • Impulsive Behavior / drug effects
  • Impulsive Behavior / physiology
  • Male
  • Memory, Short-Term / physiology
  • Methylphenidate / pharmacology
  • Mice
  • Mice, Knockout
  • Motor Activity / genetics
  • Nesting Behavior
  • Neurons / metabolism
  • Neurons / ultrastructure
  • Phenotype
  • Receptors, Dopamine / physiology
  • Substantia Nigra / metabolism
  • Synapses / ultrastructure


  • Central Nervous System Stimulants
  • Cofilin 1
  • Destrin
  • Dopamine Antagonists
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Dstn protein, mouse
  • Glutamates
  • Ppp1r1b protein, mouse
  • Receptors, Dopamine
  • Methylphenidate