Deletion of Glycogen Synthase Kinase-3β in D 2 Receptor-Positive Neurons Ameliorates Cognitive Impairment via NMDA Receptor-Dependent Synaptic Plasticity.

BACKGROUND: Cortical dopaminergic systems are critically involved in prefrontal cortex (PFC) functions, especially in working memory and neurodevelopmental disorders such as schizophrenia. GSK-3 beta (glycogen synthase kinase-3 beta) is highly associated with cAMP (cyclic adenosine monophosphate)-independent dopamine D-2 receptor (D2R)-mediated signaling to affect dopamine-dependent behaviors. However, the mechanisms underlying the GSK-3 beta modulation of cognitive function via D(2)Rs remains unclear. METHODS: This study explored how conditional cell-type-specific ablation of GSK-3 beta in D2R+ neurons (D2R-GSK-3 beta(-/-)) in the brain affects synaptic function in the medial PFC (mPFC). Both male and female (postnatal days 60-90) mice, including 140 D2R, 24 D1R, and 38 DISC1 mice, were used. RESULTS: This study found that NMDA receptor (NMDAR) function was significantly increased in layer V pyramidal neurons in mPFC of D2R-GSK-3 beta(-/-) mice, along with increased dopamine modulation of NMDAR-mediated current. Consistently, NR2A and NR2B protein levels were elevated in mPFC of D2R-GSK-3 beta(-/-) mice. This change was accompanied by a significant increase in enrichment of activator histone mark H3K27ac at the promoters of both Grin2a and Grin2b genes. In addition, altered short- and long-term synaptic plasticity, along with an increased spine density in layer V pyramidal neurons, were detected in D2R-GSK-3 beta(-/-) mice. Indeed, D2R-GSK-3 beta(-/-) mice also exhibited a resistance of working memory impairment induced by injection of NMDAR antagonist MK-801. Notably, either inhibiting GSK-3 beta or disrupting the D2R-DISC1 complex was able to reverse the mutant DISCI-induced decrease of NMDAR-mediated currents in the mPFC. CONCLUSIONS: This study demonstrates that GSK-3 beta modulates cognition via D2R-DISC1 interaction and epigenetic regulation of NMDAR expression and function.