Mice lacking p35 display hyperactivity and paradoxical response to psychostimulants.

Cyclin-dependent kinase 5/p35 kinase complex plays a critical role in dopaminergic neurotransmission. Dysregulation of dopamine (DA) signaling is associated with neurological and neuropsychiatric disorders. As cyclin-dependent kinase 5 (Cdk5) requires association with p35 for its proper activation, we hypothesized that dysregulation of Cdk5 activity might have an effect on striatal-mediated behavior. We used a mutant mouse, deficient in p35 protein (p35 KO), which displayed reduced Cdk5 activity. Throughout behavioral and biochemical characterization of naïve and psychostimulant-treated mice, we demonstrated that only juvenile p35 KO mice displayed spontaneous hyperactivity, responded with a paradoxical hypolocomotor effect to psychostimulant drugs and exhibited deficit on proper behavioral inhibition. Strong immunolabeling for tyrosine-hydroxylase and high striatal DA synthesis and contents with a low DA turnover, which were reverted by psychostimulants, were also found in mutant mice. Our results demonstrate that p35 deficiency is critically involved in the expression of a hyperactive behavioral phenotype with hyper-functioning of the dopaminergic system, emphasizing the importance of proper Cdk5 kinase activity for normal motor and emotional features. Thus, p35 KO mice may be another useful animal model for understanding cellular and molecular events underlying attention deficit hyperactivity disorder-like disorders.