Activation of Glycogen Synthase Kinase-3β Is Required for Hyperdopamine and D₂Receptor-Mediated Inhibition of Synaptic NMDA Receptor Function in the Rat Prefrontal Cortex

Abstract

The interactions between dopamine and glutamate systems play an essential role in normal brain functions and neuropsychiatric disorders. The mechanism of NMDA receptor regulation through high concentrations of dopamine, however, remains unclear. Here, we show the signaling pathways involved in hyperdopaminergic regulation of NMDA receptor functions in the prefrontal cortex by incubating cortical slices with high concentration of dopamine or administering dopamine reuptake inhibitor 1-(2-[bis-(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine (GBR12909) in vivo. We found that, under both conditions, the synaptic NMDA receptor-mediated currents were significantly attenuated by excessive dopamine stimulation through activation of D 2 receptors. Furthermore, high dose of dopamine failed to affect NMDA receptor-mediated currents after blockade of NR2B subunits but triggered a dynamin-dependent endocytosis of NMDA receptors. The high-dose dopamine/D 2 receptor-mediated suppression of NMDA receptors was involved in the increase of glycogen synthase kinase-3␤ (GSK-3␤) activity, which in turn phosphorylates ␤-catenin and disrupts ␤-catenin-NR2B interaction, but was dependent on neither Gq11 nor PLC (phospholipase C). Moreover, the hyperdopamine induced by GBR12909 significantly decreased the expression of both surface and intracellular NR2B proteins, as well as NR2B mRNA levels, suggesting an inhibition of protein synthesis. These effects were, however, completely reversed by administration of either GSK-3␤ inhibitor or D 2 receptor antagonist. These results therefore suggest that GSK-3␤ is required for the hyperdopamine/D 2 receptor-mediated inhibition of NMDA receptors in the prefrontal neurons and these actions may underlie D 2 receptor-mediated psychostimulant effects and hyperdopamine-dependent behaviors in the brain.

Disruption of hippocampal–prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission

“…Our data show that activity-dependent LTD of EPSC NMDA at the hippocampal-PFC synapse relies on endogenous activation of D2Rs. This significantly extends the physiological relevance of previous studies demonstrating that activation of D2Rs by exogenous agonists can depress NMDA agonist currents or NMDA EPSCs (27,(31)(32)(33). In contrast to the report that in 9-10-mo-old mice only a subpopulation of PFC pyramidal neurons express D2Rs (34), we found that in every case tested, LTD was D2R-dependent.…”

“…Although we were not able to confirm a role for GSK3β (27) in the D2R-dependent LTD of EPSC NMDA , our results showing that the PKA inhibitor H89 depresses EPSC NMDA are consistent with a D2R-dependent inhibition of cAMP/PKA signaling being critical for (2,11.997) = 2.4; P = 0.13]. */**/*** = P < 0.05, P < 0.01, P < 0.001, respectively.…”

“…S4E), implicating PKA inhibition in activity-dependent LTD of EPSC NMDA . Previous studies have indicated that activation of glycogen synthase kinase3-beta (GSK3β) can result in depression of NMDAR transmission (27). However, we found that LTD of EPSC NMDA was unaffected by (Fig.…”

A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health

“…[108][109][110] This is particularly intriguing since altered glutamate receptor functions have long been suspected to play a role in mental disorder pathology, mostly in schizophrenia. 73,111 However, it would be premature to conclude that the role of Akt-GSK3 signalling is restricted to the regulation of glutamate receptor functions.…”

The Unique Properties of the Prefrontal Cortex and Mental Illness

“…Accordingly, there have been considerable efforts by many groups to understand the cellular mechanisms of DA modulation in PFC neurons [49,50,[55][56][57][58][59][60]. Although the results of these efforts sometimes lead to contradictions and controversies, these studies from both in vivo and in vitro experiments have provided some principal features and mechanisms of DA modulation in the PFC circuitry [49].…”