Development of Hyperactivity and Anxiety Responses in Dopamine Transporter-Deficient Mice

Abstract

Dopamine (DA) is a catecholamine neurotransmitter that regulates many aspects of motivated behavior in animals. Extracellular DA is highly regulated by the presynaptic high-affinity dopamine transporter (DAT), and drug- or genetically induced deficiencies in DAT function result in loss of DA reuptake. Mice in which DAT expression has been ablated have been previously proposed to be a relevant model of attention deficit hyperactivity disorder and have led to mechanistic insights regarding psychostimulant drug actions. However, very little previous work has emphasized the biobehavioral development of DAT-deficient mice. We therefore examined motoric, emotional and cognitive phenotypes in preadolescent (P22–26) DAT mutant mice. Consistent with previous reports in adult DAT^–/– mice, we observed a hyperlocomotive phenotype in preadolescent mice across multiple assays. Somewhat surprisingly, spatial working memory in a Y-maze appeared intact, suggesting that cognitive phenotypes may emerge relatively late in development following hyperdopaminergia. Anxiety levels appeared to be reduced in DAT^–/– mice, as defined by elevated plus maze and light-dark preference assays. No significant differences were observed between wild-type and heterozygous mice, suggesting a minimal impact of DAT haploinsufficiency on neurobehavioral status. Taken together, these data for the first time establish behavioral phenotypes of DAT mutant mice during development and suggest complex developmental stage-dependent effects of DA signaling on cognitive and emotional behaviors.

Developmental pesticide exposure reproduces features of attention deficit hyperactivity disorder

“…With regard to additional behaviors, mice developmentally exposed to deltamethrin show deficits in Y-maze performance, indicative of working memory and attention deficits. However, no change in performance was observed in DAT knockout mice (54). The discrepancies observed between different DAT knockout and overexpression models, the SHR, and our results may lie in the neuroanatomical specificity of the alterations in DAT levels.…”

Developmental origins of brain disorders: roles for dopamine

“…For example, a functional hyperdopaminergia, which occurs in DA transporter (DAT) knockout mice, leads to a loss of proximal dendritic spines in striatal projection neurons (Berlanga et al, 2011). This model also shows a behavioral phenotype of hyperactivity and anxiety as well as altered mesocortical circuitry (Zhang et al, 2010; Carpenter et al, 2012), and DA dysregulation occurs not only during development, but continues into adulthood in this model. Primate and rodent models of DA depletion also show decreases in striatal dendritic spines (Ingham et al, 1989; Neely et al, 2007; Villalba et al, 2009).…”

Conditional deletion of Ndufs4 in dopaminergic neurons promotes Parkinson’s disease-like non-motor symptoms without loss of dopamine neurons

“…These non-motor symptoms may start in the early stages of the Parkinson’s disease prior to the onset of motor symptoms394041. Though the degeneration of serotonergic and noradrenergic neurons may underlie these non-motor symptoms, dopamine transporter-deficient mice exhibit hyperactivity and anxiety responses, suggesting that dysfunction of the dopamine pathway may also contribute4243444546. In this study, we used Ndufs4 cKO mice to investigate the effects of complex I dysfunction on non-motor symptoms associated with Parkinson’s disease34.…”