Humanized dopamine D_4.7 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 (D4.7R) 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 D4.7R 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 D4.7R mice, with the long third intracellular domain of the human D4.7R, may provide a valuable tool to examine the relationship between the D4.7R variant and specific behavioral phenotypes. We report that D4.7R male mice carrying the humanized D4.7R 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, D4.7R 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 D4.7R variant and specific behaviors and encourage further consideration of dopamine D4 receptor (DRD4) ligands as novel treatments for psychiatric disorders in which D4.7R has been implicated.