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

ABSTRACT: 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.

SUBMITTER: Deng S

PROVIDER: S-EPMC4674704 | biostudies-other | 2015 Dec

REPOSITORIES: biostudies-other

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Project description:BACKGROUND:Over-stimulation of dopamine signaling is thought to underlie the pathophysiology of a list of mental disorders, such as psychosis, mania and attention-deficit/hyperactivity disorder. These disorders are frequently associated with cognitive deficits in attention or learning and memory, suggesting that persistent activation of dopamine signaling may change neural plasticity to induce cognitive or emotional malfunction. METHODS:Dopamine transporter knockdown (DAT-KD) mice were used to mimic a hyper-dopamine state. Novel object recognition (NOR) task was performed to assess the recognition memory. To test the role of dopamine D3 receptor (D3R) on NOR, DAT-KD mice were treated with either a D3R antagonist, FAUC365 or by deletion of D3R. Total or phospho-GSK3 and -ERK1/2 signals in various brain regions were measured by Western blot analyses. To examine the impact of GSK3 signal on NOR, wild-type mice were systemically treated with GSK3 inhibitor SB216763 or, micro-injected with lentiviral shRNA of GSK3? or GSK3? in the medial prefrontal cortex (mPFC). RESULTS:We confirmed our previous findings that DAT-KD mice displayed a deficit in NOR memory, which could be prevented by deletion of D3R or exposure to FAUC365. In WT mice, p-GSK3? and p-GSK3? were significantly decreased in the mPFC after exposure to novel objects; however, the DAT-KD mice exhibited no such change in mPFC p-GSK3?/? levels. DAT-KD mice treated with FAUC365 or with D3R deletion exhibited restored novelty-induced GSK3 dephosphorylation in the mPFC. Moreover, inhibition of GSK3 in WT mice diminished NOR performance and impaired recognition memory. Lentiviral shRNA knockdown of GSK3?, but not GSK3?, in the mPFC of WT mice also impaired NOR. CONCLUSION:These findings suggest that D3R acts via GSK3? signaling in the mPFC to play a functional role in NOR memory. In addition, treatment with D3R antagonists may be a reasonable approach for ameliorating cognitive impairments or episodic memory deficits in bipolar disorder patients.

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

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