Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase identified by its close sequence homology to the classic members of the cdk family of regulating cell cycle progression proteins. Cdk5 is a unique member of this family that is active in post-mitotic neurons. Like other Cdks, however, monomeric Cdk5 shows no enzymatic activity and requires association with a regulatory subunit, either p35 or p39, which are brain-specific (Ishiguro et al. 1994;Lew et al. 1994;Tsai et al. 1994;Tang et al. 1995). Moreover, in vivo evidence has demonstrated that the level of p35 regulating protein is a rate-limiting factor for the up-regulation of Cdk5 activity (Takahashi et al. 2005). Several lines of evidence suggest that the Cdk5/p35 complex plays a critical role in normal brain development, regulating neuronal migration and differentiation, axodendritic organization and laminar architecture, trafficking and transport (Nikolic et al. 1996;Ohshima et al. 1996;Chae et al. 1997;Paglini et al. 1998;Ratner et al. 1998;Kwon and Tsai 1998;Ohshima et al. 1999;Kwon et al. 1999;Smith and Tsai 2002;Dhariwala and Rajadhyaksha 2008). Besides its essential role in brain development, Cdk5 has also been implicated in dopaminergic transmission in the post-natal brain, where it modulates Received January 18, 2010; revised manuscript received April 6, 2010; accepted April 7, 2010. Address correspondence and reprint requests to Gabriela Paglini, PhD, Laboratory of Neurobiology and Cell Biology, Instituto de Investigación Médica Mercedes y Martín Ferreyra (INIMEC-CONICET), Av. Friuli 2434, 5016 Có rdoba Argentina. E-mail: gpaglini@immf.uncor.eduAbbreviations used: ADHD, attention deficit hyperactivity disorder; Amph, D-anphetamine sulfate; Cdk5, cyclin-dependent kinase 5; CPu, striatum-caudate putamen; DA, dopamine; DARPP-32, dopamine and cAMP regulated phosphoprotein, molecular mass 32 kDa; DOPAC, 3,4-dihydroxyphenylacetic acid; EPM, elevated plus maze; Mtph, methylphenidate; NAc, nucleus accumbens; NHS, normal horse serum; PBS, phosphate-buffered saline; PKA, cAMP-dependent kinase; TBST, trisbuffered saline-tween 20; TH, tyrosine hydroxylase; WT, wild type. AbstractCyclin-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 psychostimulanttreated 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 ...

The cellular and molecular mechanisms of sensitization in the addictive process are still unclear. Recently, chronic treatment with cocaine has been shown to upregulate the expression of cyclin-dependent kinase 5 (cdk5) and its specific activator, p35, in the striatum, as a downstream target gene of DeltaFosB, and has been implicated in compensatory adaptive changes associated with psychostimulants. Cdk5 is a serine/threonine kinase and its activation is achieved through association with a regulatory subunit, either p35 or p39. P35 is cleaved by the protease calpain, which results in the generation of a truncated product termed p25, which contains all elements necessary for cdk5 activation. The cdk5/p35 complex plays an essential role in neuronal development and survival. It has also been involved in neuronal trafficking and transport and in dopaminergic transmission, indicating its role either in presynaptic and postsynaptic signaling. In this study we report that the cdk5/p35 complex participates in acute and chronic d-amphetamine (AMPH)-evoked behavioral events, and we show a surprisingly transient enhanced expression of p25 and a lasting increased expression of p35 in dorsal striatal synaptosomes after acute and chronic AMPH administration. Pak1, a substrate for cdk5, is also enriched in the synaptosomal fraction of acute AMPH-treated rats. Our data suggest that the transient upregulation of p25 may regulate the activity of cdk5 in phosphorylating particular substrates, such as Pak1, implicated in the compensatory adaptive morphophysiologic changes associated with the process of behavioral sensitization to psychostimulants.

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