Dopamine D3 receptor and GSK3β signaling mediate deficits in novel object recognition memory within dopamine transporter knockdown mice

Abstract

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 D 3 receptor (D 3 R) on NOR, DAT-KD mice were treated with either a D 3 R antagonist, FAUC365 or by deletion of D 3 R. 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). Results: We confirmed our previous findings that DAT-KD mice displayed a deficit in NOR memory, which could be prevented by deletion of D 3 R 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 D 3 R 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. Conclusion:These findings suggest that D 3 R acts via GSK3β signaling in the mPFC to play a functional role in NOR memory. In addition, treatment with D 3 R antagonists may be a reasonable approach for ameliorating cognitive impairments or episodic memory deficits in bipolar disorder patients.

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

“…It has been found that the deletion of D3R in DAT knockdown mice restores novelty-induced GSK3β activation in the medial PFC. Moreover, inhibition or knockdown of GSK3β, but not the α isozyme, in the medial PFC of wild-type mice impairs recognition memory [160], which suggests that in the medial PFC, D3R acts via GSK3β signaling to play a role in the novel objects recognition memory.…”

“…Hyper-dopaminergic mice display concomitant novelty-induced locomotor hyperactivity [157], which could be reduced by GSK3 inhibitors in the DAT lacking mice, and in amphetamine-treated normal mice [158,159]. Additionally, the inhibitory Ser9-phosphorylation of GSK3β is decreased in murine medial PFC after exposure of animals to novel objects, but the DAT knockdown mice exhibit no such decrease [160]. It has been found that the deletion of D3R in DAT knockdown mice restores novelty-induced GSK3β activation in the medial PFC.…”

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

“…Beyond the well-known negative regulation of adenylyl cyclase, the D3R is involved in other, G-protein-independent intracellular signaling processes (e.g., GRK, ß-arrestin, GSK3, Akt, etc., see also in Section 5 ). Exposure to novelty such as in the novel object recognition task, is associated with the dephosphorylation of the two GSK3 kinase isoforms in the medial prefrontal cortex of mice [ 202 ]. GSK3 dephosphorylation is practically eliminated in DA transporter knockdown mice that also show deficits in novel object recognition performance, both of which can be rescued either by the genetic knockout of the D3R or the administration of the D3R antagonist FAUC365 [ 202 ].…”

“…Exposure to novelty such as in the novel object recognition task, is associated with the dephosphorylation of the two GSK3 kinase isoforms in the medial prefrontal cortex of mice [ 202 ]. GSK3 dephosphorylation is practically eliminated in DA transporter knockdown mice that also show deficits in novel object recognition performance, both of which can be rescued either by the genetic knockout of the D3R or the administration of the D3R antagonist FAUC365 [ 202 ]. Conversely, stimulation of D3Rs by the D2R/D3R agonist quinelorane causes a rapid and transient increase in the phosphorylation of GSK3, Akt and mTORC1 effectors in the nucleus accumbens and dorsal striatum in rats in vivo which can be prevented by the administration of the D3R antagonist S33084 [ 263 ].…”

A New Paradigm for Training Hyperactive Dopamine Transporter Knockout Rats: Influence of Novel Stimuli on Object Recognition

“…Novel object recognition was found to depend on D2 DA receptor activity ( França et al, 2016 ). In DAT knockdown mice, the impairment of novel object recognition was observed ( Chang et al, 2020 ).…”