Hyperlocomotion is observed in both the home cage and novel open-field. These mice have working-memory deficits, as indicated by an increase in the number of revisits to the maze arms in the eight-arm radial maze and in the Y maze spontaneous alternation test. Impulsive behavior is observed in the elevated plus maze. While all control and single-mutant mice remained on the maze for the entire testing period

(300 s), 89% of the ACC mice jumped off the elevated plus maze. Both the hyperlocomotion and impulsive phenotypes are attenuated by methylphenidate. Electron microscopic analyses reveals morphologic abnormalities in striatal excitatory synapses (reduced synapse density, larger button Ribociclib in vitro and spine structures,

and increased TGF-beta inhibitor review numbers of docked vesicles) in ACC mice but not in single-mutant mice [52••]. Interestingly, blockade of glutamate transmission with dizocilpine, an N-methyl-d-aspartate receptor antagonist, attenuates hyperlocomotion of the ACC mice. Zimmerman et al. argued that an inhibitory and excitatory transmission (I/E) imbalance in striatal circuits has a crucial role in the pathogenesis of ADHD [52••]. G-protein-coupled receptor kinase-interacting protein-1 (GIT1) is a GTPase-activating protein for the ADP ribosylation factor that interacts with multiple signaling and adaptor proteins 53 and 54]. A human study demonstrated the association of an intronic SNP with ADHD [55], although another study failed to replicate the finding [56]. GIT1-KO mice exhibit hyperactivity and impaired learning and memory. They also have enhanced

electroencephalogram theta rhythms. Amphetamine normalizes all these phenotypes, supporting the applicability of these Phosphoribosylglycinamide formyltransferase mice as an ADHD model, although attention deficits and impulsivity were not directly assessed [55]. At the cellular level, inhibitory transmission (I) but not excitatory transmission (E) is attenuated at GIT1-KO synapses, leading to an I/E imbalance [55]. Lee and Silva discussed the significance of an I/E imbalance in ADHD together with findings in neurofibromatosis type 1 (NF1)-KO mice [57]. NF1, caused by mutations in the gene encoding neurofibromin, a p21Ras GTPase-activating protein, is associated with ADHD [58]. Indeed, NF1-KO mice have an I/E imbalance as well as attention deficits in the lateralized reaction time task 59 and 60]. The gamma aminobutyric acid transporter (GAT) terminates the actions of GABA in the synaptic cleft. GAT subtype 1 (GAT1) is the major isoform in the central nervous system [61]. GAT1-KO mice are hyperactive and exhibit deficits in spatial reference memory [61]. In an incentive runway test, GAT1-KO mice showed impaired attentional focusing compared to wild-type and heterozygous mice [62]. GAT1-KO mice also exhibited impulsivity in an incentive passive avoidance test [62].