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

Abstract

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.

ADF/cofilin: a crucial regulator of synapse physiology and behavior

“…Such changes could be caused by defective vesicle recruitment, which indeed was shown by reduced depolarization-induced glutamate release from synaptosomes of double mutants and by stronger synaptic depletion during 10 Hz stimulation for 2 min [24]. Interestingly, the defects in the distribution, recruitment and exocytosis of synaptic vesicles were evident only in double mutants, but not in ADF or cofilin1 single mutants [18,21,24,25]. Hence, ADF and cofilin1 have the capacity to compensate the others' inactivation in presynaptic terminals, which is in line with elevated synaptic cofilin1 levels in ADF mutants and, vice versa, elevated synaptic ADF levels in cofilin1 mutants [18,21].…”

“…A role of ADF/cofilin in spatial learning has been further corroborated by elevated spine numbers with high levels of phosphorylated (inactive) ADF/cofilin in the rat hippocampal CA1 region upon unsupervised learning in an enriched environment [32]. Notably, while long-term spatial memory was impaired in cofilin1 mutants, short-term spatial working memory was fully intact [21,25]. Thus, cofilin1 mutant mice provide a genetic proof for the dissociation of short-and long-term spatial memory processes, thereby confirming the previously postulated existence of two distinct mechanisms for spatial memory [66].…”

“…In double mutants lacking ADF and cofilin1, the number of synaptic vesicles attached to the active zone was increased and consequently synaptic vesicle exocytosis was enhanced [24,25]. In line with a role of ADF/cofilin in vesicle exocytosis, inactivation of upstream regulators such as RhoB, ROCK2, PAK, LIMK1 or slingshot impaired vesicle exocytosis [30,44,50,51,63].…”

“…The most obvious explanation for this discrepancy is compensation of ADF inactivation in mice, which has been corroborated by elevated synaptic cofilin1 levels [18]. Indeed, compared to cofilin1 mutants, spine size was increased in the hippocampus and the striatum of double mutants lacking both ADF and cofilin1 [24,25], thereby demonstrating a role of ADF in spine morphology and overlapping, and redundant function for ADF and cofilin1 in dendritic spines. In line with these data, compound short hairpin RNA-mediated knockdown of cofilin1 and ADF, but not of cofilin1 alone, compromised spine enlargement during initial LTP in hippocampal slices, and this effect was rescued by the reexpression of cofilin1 [23].…”

“…Cofilin1 and ADF are broadly expressed in the adult brain [9,18], they are both present at excitatory synapses [18,19], and their synaptic function has been investigated in numerous recent studies. These studies established that (1) ADF/cofilin is critical for spine morphology [20][21][22][23], (2) ADF/cofilin controls functional and structural aspects of synaptic plasticity [4,[21][22][23], (3) cofilin1 and ADF have redundant and overlapping functions in neurotransmitter release [24,25], and (4) genetic inactivation of cofilin1 and ADF impairs learning and causes severe behavioral abnormalities [21,25,26]. Moreover, a number of regulatory pathways upstream of ADF/cofilin in excitatory synapses have been identified.…”