Neurobiology/Neurophysiology Group (A-MZ, TJ, MW, AG, MBR) University of Kaiserslautern, Kaiserslautern, Germany.
Institute of Genetics (CBG, WW), University of Bonn, Bonn, Germany.
Biol Psychiatry. 2015 Jul 15;78(2):95-106. doi: 10.1016/j.biopsych.2014.03.011. Epub 2014 Mar 21.
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.
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.
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.
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.
肌动蛋白解聚蛋白（ADF/cofilin）家族的肌动蛋白解聚蛋白对于肌动蛋白动力学至关重要，而肌动蛋白动力学对于突触功能至关重要。ADF/cofilin 家族的两个成员，ADF 和 n-cofilin，在大脑中含量非常丰富，存在于兴奋性突触中。先前的研究表明 n-cofilin 与突触后可塑性、联想学习和焦虑有关。这些研究还表明 ADF 和 n-cofilin 具有重叠的功能。
我们对 ADF 和 n-cofilin 单突变体和双突变体（命名为 ACC 小鼠）进行了药理学行为、电生理和电子显微镜研究，以表征 ADF/cofilin 活性对突触生理学和小鼠行为的重要性。
ACC 小鼠，但不是单突变体，表现出过度活跃、冲动和工作记忆受损。安非他命，一种常用于治疗注意力缺陷多动障碍（ADHD）的精神兴奋剂，可逆转过度活跃和冲动行为。此外，ACC 小鼠表现出纹状体兴奋性突触的形态紊乱，伴有谷氨酸释放的强烈增加。多巴胺或谷氨酸传递的阻断导致正常的运动。
我们的研究表明，ADHD 可能是由于纹状体回路中兴奋和抑制之间的平衡失调引起的，为这种神经行为障碍的机制提供了新的见解。我们的结果将肌动蛋白动力学与 ADHD 联系起来，表明肌动蛋白调节蛋白的突变可能导致人类 ADHD 的病因。
