Abstract
BackgroundOver-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.MethodsDopamine 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 GSK3β or GSK3α in the medial prefrontal cortex (mPFC).ResultsWe 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-GSK3α and p-GSK3β were significantly decreased in the mPFC after exposure to novel objects; however, the DAT-KD mice exhibited no such change in mPFC p-GSK3α/β 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 GSK3β, but not GSK3α, in the mPFC of WT mice also impaired NOR.ConclusionThese findings suggest that D3R acts via GSK3β 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.
Highlights
Bipolar disorder (BD) is often accompanied by progressive impairment in many cognitive components, such as attention, memory and executive function [1], with BD patients showing poor performance on learning and memory tasks especially during the manic phase [2, 3]
D3 receptor (D3R) blockade or deletion reverses Dopamine transporter knockdown (DAT-KD)-induced Novel object recognition (NOR) deficit To validate our previous finding that DA transporter (DAT)-KD induces D3R-dependent object recognition deficits, a NOR test was administered to WT, DAT-KD, FAUC365-treated DAT-KD (3 mg/kg, s.c., 10 min before training) and D3R-KO/DAT-KD double mutant mice
The DAT-KD mice showed a higher horizontal locomotor activity compared to the WT mice during the NOR training trial (p < 0.05), but locomotion was not affected by D3R blockade or deletion (p > 0.05; Additional file 1: Figure S1C)
Summary
Bipolar disorder (BD) is often accompanied by progressive impairment in many cognitive components, such as attention, memory and executive function [1], with BD patients showing poor performance on learning and memory tasks especially during the manic phase [2, 3]. DAT-KD mice exhibit aberrant cortical glutamatergic afferents and display mania-like behaviors [9,10,11] Both DAT-KD and wild-type (WT) mice treated with the DA reuptake inhibitor, GBR12909, exhibit deficits in novel object recognition (NOR) memory [12]. 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
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