"Inducible deletion of dopamine D2 receptors in adult mice triggers a Parkinsonian-like motor syndrome."

BELLO GAY, E; NOAÍN, D; GELMAN, D; RODRÍGUEZ, V; RUBINSTEIN, M

Hotel Casa Serrana, Huerta Grande, Córdoba, Argentina

Congreso; I Reunión Conjunta de Neurociencias (IRCN); 2009

Mouse gene knockout technology has been one of the major breakthroughs of the last 20 years for in vivo gene functional studies. Although many insights have been gained from numerous reports, we also learned the limitations of this technology such as the occurrence of compensatory adaptations to the absence of the gene product that leads to alternative developmental programs. For example, mice carrying null alleles for the dopamine D2 receptor (D2R) develop compensations that produce a hypolocomotor state that is much less severe than that induced by the acute pharmacological blockade of D2Rs in wild-type mice. To study the participation of D2Rs in normally developed adult mice, we created inducible Drd2 null mutant mice by crossing Drd2flox/flox mice with transgenic mice ubiquitously expressing cre recombinase fused to a mutated ligand binding domain of the estrogen receptor (Cre-ERTM). Tamoxifen binding to cytosolic Cre-ERTM translocates into the nucleus promoting excision of the critical coding exon 2 of Drd2. Two-month old compound Drd2flox/flox.Cre-ERTM (indDrd2KO) mice were injected with 50 mg/kg tamoxifen for 10 days. Three weeks later the number of D2Rs in indDrd2KO mice was 80 lower as determined by [3H]nemonapride binding. IndDrd2KO mice displayed a Parkinsonian-like phenotype characterized by resting tremor, inability to negotiate on a rotarod, lack of movement on a suspension bar and a 75 drop in locomotor activity due to fewer movement initiations. IndDrd2KO mice showed decreased responses haloperidol and amphetamine. Thus, loss of D2Rs in adult mice produces motor deficits that are much more severe than those observed in classical Drd2 knockout mice revealing the real importance of D2R function.