Mice lacking p35 display hyperactivity and paradoxical response to psychostimulants

FAVIO ARIEL KRAPACHER; ESTELA CECILIA MLEWSKI; SOLEDAD FERRERAS; VICTORIA PISANO; MARIANA PAOLOROSSI; CRISTIAN HANSEN; GABRIELA PAGLINI

JOURNAL OF NEUROCHEMISTRY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2010 vol. 114 p. 203 - 214

0022-3042

Abstract Cdk5/p35 kinase complex plays a critical role in dopaminergic neurotransmission. Dysregulation of DA signaling is associated with neurological and neuropsychiatric disorders. Since Cdk5 requires association with p35 for its proper activation, we hypothesized that dysregulation of Cdk5 activity might have an effect on striatalmediated 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 ADHD-like disorders.Cdk5/p35 kinase complex plays a critical role in dopaminergic neurotransmission. Dysregulation of DA signaling is associated with neurological and neuropsychiatric disorders. Since Cdk5 requires association with p35 for its proper activation, we hypothesized that dysregulation of Cdk5 activity might have an effect on striatalmediated 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 ADHD-like disorders.