Deletion of Glycogen Synthase Kinase-3β in D₂ 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-3β (glycogen synthase kinase-3β) is highly associated with cAMP (cyclic adenosine monophosphate)–independent dopamine D₂ receptor (D₂R)-mediated signaling to affect dopamine-dependent behaviors. However, the mechanisms underlying the GSK-3β modulation of cognitive function via D₂Rs remains unclear. Methods: This study explored how conditional cell-type–specific ablation of GSK-3β in D₂R+ neurons (D₂R-GSK-3β^−/−) 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-3β^−/− mice, along with increased dopamine modulation of NMDAR-mediated current. Consistently, NR2A and NR2B protein levels were elevated in mPFC of D₂R-GSK-3β^−/− 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-3β^−/− mice. Indeed, D₂R-GSK-3β^−/− mice also exhibited a resistance of working memory impairment induced by injection of NMDAR antagonist MK-801. Notably, either inhibiting GSK-3β or disrupting the D₂R-DISC1 complex was able to reverse the mutant DISC1-induced decrease of NMDAR-mediated currents in the mPFC. Conclusions: This study demonstrates that GSK-3β modulates cognition via D₂R-DISC1 interaction and epigenetic regulation of NMDAR expression and function.