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Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits.

ABSTRACT: Mice deficient for dopamine D(2) and D(3) receptors exhibit blunted c-fos responses to D(1) agonist stimulation. Stereologic cell counting revealed decreased numbers of medial prefrontal cortex neurons that express Fos immunoreactivity in all layers, particularly in the prelimbic and anterior cingulate subregions. Pretreatment of these mutants with a single, low dose of methamphetamine (METH) led to a sustained increase in the number of neurons that express Fos immunoreactivity in response to a D(1) agonist challenge, which was most significant in prelimbic and anterior cingulate subregions. The increased c-fos responses reached wild-type-like levels in METH-pretreated D(2) mutants but remained submaximal in METH-pretreated D(3) mutants. Additional studies tested the performance of wild type and mutants in a delayed alternation test, a cognitive task critically dependent on optimal activation of prefrontal cortical D(1) receptors by synaptically released dopamine. Both D(2) and D(3) mutants exhibited deficits in their spatial working memory, with increasing impairments at increasing delays. Whereas METH pretreatment rescued the spatial working memory of D(2) mutants, it had no effect on D(3) mutants. These data suggest that the sustained improvement of spatial working memory in METH-pretreated D(2) mutants is attributable to D(1) receptor-mediated mechanisms.

SUBMITTER: Glickstein SB

PROVIDER: S-EPMC6758242 | biostudies-literature | 2002 Jul

REPOSITORIES: biostudies-literature

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Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits.

Glickstein Sara B SB Hof Patrick R PR Schmauss Claudia C

The Journal of neuroscience : the official journal of the Society for Neuroscience 20020701 13

Mice deficient for dopamine D(2) and D(3) receptors exhibit blunted c-fos responses to D(1) agonist stimulation. Stereologic cell counting revealed decreased numbers of medial prefrontal cortex neurons that express Fos immunoreactivity in all layers, particularly in the prelimbic and anterior cingulate subregions. Pretreatment of these mutants with a single, low dose of methamphetamine (METH) led to a sustained increase in the number of neurons that express Fos immunoreactivity in response to a ...[more]

PMID: 12097513

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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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Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits.

Publications

Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits.

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