Mice lacking p35 exhibit hyperactivity, paradoxical response to psychostimulants and dopamine signaling deregulation: a potential mouse model of Attention Deficit with Hyperactivity Disorder?

KRAPACHER, FA; FERRERAS, S; HANSEN, C; PAGLINI, G.

Buzios, Brasil

Congreso; I Congress IBRO/LARC of Neurosciences for Latin America, Caribbean and Iberian Peninsula.; 2008

Attention deficit/hyperactivity disorder (ADHD) is the main psychiatric disorder affecting the 12% worldwide scholar age children. These kids display inappropriate levels of inattention, hyperactivity, and impulsivity that cause impairment in intellectual functioning. Drugs that regulate dopamine (DA) transmission, like psychostimulants (methylphenidate, d-amphetamine) are the usual and effective medicaments in ameliorate the behavioural symptoms. DA and components of catecholamine signalling are the first candidates in the ADHD aetiology. Considering that cdk5/p35 complex participates in membrane trafficking, endocytosis, drug addiction, and plays a critical role in dopaminergic transmission, we were encouraged to think a possible association of cdk5/p35 with ADHD. Objective: Investigate a possible role for cdk5/p35 in ADHD neurobiology. Methods: Transgenic mice deficient in p35 (p35KO) and WT were tested in an open field, treated or not with psychostimulants, and elevated plus maze. Expression levels of Tyrosine hydroxilase (TH), DA transporter (DAT) and D1 receptor were determinate in striatum and prefrontal cortex by western blot (WB). DA levels and its metabolites were quantified by liquid chromatography in these brain tissues. TH immunohistochemistry in brain sections were performed in both genotypes. Results: P35KO exhibited spontaneous hyperactivity and paradoxical response to psychostimulants. In the plus maze, p35KO mice did not manifest any behavioral sign of approach/avoidance conflict, entering indiscriminately into either protected or unprotected areas, indicating a deficit on proper behavioral inhibition. WB analysis revealed a significant increase of TH in striatum compared with WT, as well as a strong immunoreactivity in this area of brain sections, and raised levels of DA and its metabolites. Different expression levels of D1 and DAT were found between genotypes. Conclusions: These results suggests a strong association of cdk5/p35 with ADHD. We propose p35KO mouse as a novel animal model of ADHD, that fulfills many of the validation criteria for assessing ADHD models and they may also provide some useful insights into the basis neural pathways that subserve ADHD-like behaviors.