Lack of Cdk5 activity is involved on Dopamine Transporter expression and function: Evidences from an animal model of Attention-Deficit Hyperactivity Disorder

FERNÁNDEZ GUILLERMO; MARI MACARENA MARIEL; QUASSOLLO GONZALO; PAGLINI MARÍA GABRIELA

Virtual

Congreso; XXXVI Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2021

Sociedad Argentina de Investigación en Neurociencias (SAN)

Attention deficit/Hyperactivity disorder (ADHD) is one of the most diagnosed psychiatric disorders. The core symptoms include hyperactivity, impulsiveness and inattention. The main pharmacological treatment consists of psychostimulant drugs affecting Dopamine Transporter (DAT) function. We have shown that mice lacking p35 (p35KO) which have reduced Cdk5 activity, present key hallmarks resembling those described in animal models of ADHD. The p35KO mouse displays spontaneous hyperactivity and shows a calming effect of psychostimulant treatment. Besides, Dopamine (DA) neurotransmission is altered in these mice as they have an increased DA content with a low DA turnover. This led us to hypothesize that the lack of Cdk5 activity affects DAT expression and/or function. We performed biochemical assays, cell-based approaches, quantitative fluorescence analysis and functional studies that allowed us to demonstrate that p35KO mice exhibit decreased DA uptake and reduced cell surface DAT expression in striatum. These findings are supported by in vitro observations in which the inhibition of Cdk5 in N2a cells induced a significant increase in constitutive DAT endocytosis with a concomitant increase in DAT localization to recycling endosomes. These data provide evidences regarding the role of Cdk5/p35 in DAT expression and function, thus contributing to the knowledge of DA neurotransmission physiology and also providing therapeutic options for the treatment of DA pathologies such as ADHD.