Humanized dopamine D4.7 receptor male mice display risk-taking behavior and deficits of social recognition and working memory in light/dark-dependent manner

Abstract

The dopamine D₄ receptor 7-repeat allele (D_4.7R) has been linked with psychiatric disorders such as attention-deficit–hyperactivity disorder, autism, and schizophrenia. However, the highly diverse study populations and often contradictory findings make it difficult to draw reliable conclusions. The D_4.7R has the potential to explain individual differences in behavior. However, there is still a great deal of ambiguity surrounding whether it is causally connected to the etiology of psychiatric disorders. Therefore, humanized D_4.7R mice, with the long third intracellular domain of the human D_4.7R, may provide a valuable tool to examine the relationship between the D_4.7R variant and specific behavioral phenotypes. We report that D_4.7R male mice carrying the humanized D_4.7R variant exhibit distinct behavioral features that are dependent on the light–dark cycle. The behavioral phenotype was characterized by a working memory deficit, delayed decision execution in the light phase, decreased stress and anxiety, and increased risk behavior in the dark phase. Further, D_4.7R mice displayed impaired social recognition memory in both the light and dark phases. These findings provide insight into the potential causal relationship between the human D_4.7R variant and specific behaviors and encourage further consideration of dopamine D₄ receptor (DRD4) ligands as novel treatments for psychiatric disorders in which D_4.7R has been implicated.