Attention-Deficit/Hyperactivity Disorder-like Phenotype in a Mouse Model with Impaired Actin Dynamics.
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.
Neurobiology/Neurophysiology Group (A-MZ, TJ, MW, AG, MBR) University of Kaiserslautern, Kaiserslautern, Germany.
Anika-Maria
AM
Zimmermann
Neurobiology/Neurophysiology Group (A-MZ, TJ, MW, AG, MBR) University of Kaiserslautern, Kaiserslautern, Germany.
Tanja
T
Jene
Neurobiology/Neurophysiology Group (A-MZ, TJ, MW, AG, MBR) University of Kaiserslautern, Kaiserslautern, Germany.
Michael
M
Wolf
Neurobiology/Neurophysiology Group (A-MZ, TJ, MW, AG, MBR) University of Kaiserslautern, Kaiserslautern, Germany.
Andreas
A
Görlich
Institute of Genetics (CBG, WW), University of Bonn, Bonn, Germany.
Christine B
CB
Gurniak
Department of Neuroscience (MS-P), University of Turin, Turin, Italy.
Marco
M
Sassoè-Pognetto
Institute of Genetics (CBG, WW), University of Bonn, Bonn, Germany.
Walter
W
Witke
Animal Physiology Group (EF), University of Kaiserslautern, Kaiserslautern, Germany.
Eckhard
E
Friauf
Neurobiology/Neurophysiology Group (A-MZ, TJ, MW, AG, MBR) University of Kaiserslautern, Kaiserslautern, Germany; Institute of Physiological Chemistry (MBR), University of Marburg, Marburg, Germany. Electronic address: marco.rust@staff.uni-marburg.de.
Marco B
MB
Rust
D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D051338:Cofilin 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003342:Corpus Striatum / Q000648:ultrastructure*; D051345:Destrin / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials; D005971:Glutamates / Q000378:metabolism; D007175:Impulsive Behavior / Q000187:drug effects / Q000502:physiology; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D008774:Methylphenidate / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009425:Nesting Behavior; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D010641:Phenotype; D011954:Receptors, Dopamine / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism; D013569:Synapses / Q000648:ultrastructure
D000697:Central Nervous System Stimulants; D051338:Cofilin 1; D051345:Destrin; D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C495825:Dstn protein, mouse; D005971:Glutamates; C497929:Ppp1r1b protein, mouse; D011954:Receptors, Dopamine; D008774:Methylphenidate
ADF; ADHD; Actin dynamics; Hyperactivity; Locomotion; n-cofilin