A behavioral defect of temporal association memory in mice that partly lack dopamine reuptake transporter

Temporal association memory, like working memory, is a type of episodic memory in which temporally discontinuous elements are associated. However, the mechanisms that govern this association remain incompletely understood. Here, we identify a crucial role of dopaminergic action in temporal association memory. We used hemizygote hyperdopaminergic mutant mice with reduced dopamine transporter (DAT) expression, referred to as DAT(+/-) mice. We found that mice with this modest dopamine imbalance exhibited significantly impaired trace fear conditioning, which necessitates the association of temporally discontinuous elements, and intact delay auditory fear conditioning, which does not. Moreover, the DAT(+/-) mice displayed substantial impairments in non-matching-to-place spatial working-memory tasks. Interestingly, these temporal association and working memory deficits could be mimicked by a low dose of the dopamine D2 receptor antagonist haloperidol. The shared phenotypes resulting from either the genetic reduction of DAT or the pharmacological inhibition of the D2 receptor collectively indicate that temporal association memory necessitates precise regulation of dopaminergic signaling. The particular defect in temporal association memory due to partial lack of DAT provides mechanistic insights on the understanding of cognitive impairments in multiple neurodevelopmental disorders.