Deletion of Glycogen Synthase Kinase-3β in D2 Receptor-Positive Neurons Ameliorates Cognitive Impairment via N-Methyl-D-Aspartate Receptor-Dependent Synaptic Plasticity

Abstract Background Cortical dopaminergic systems are critically involved in prefrontal cortex (PFC) functions, especially in working memory and neurodevelopmental disorders such as schizophrenia (SZ). Glycogen synthase kinase-3β (GSK-3β) is highly associated with cAMP-independent dopamine (DA) D2 receptor (D2R)-mediated signaling to affect DA-dependent behaviors. However, the mechanisms underlying the GSK-3β modulation of cognitive function via D2Rs remains unclear. Methods We 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. Both male and female (P60-P90) mice, including 140 D2R-, 24 D1R-, and 38 DISC1-mice were used. Results We found that NMDAR function was significantly increased in layer V pyramidal neurons in mPFC of D2R-GSK-3β-/- mice, along with increased DA 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 acute 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 Our study demonstrates that GSK-3β modulates cognition via D2R-DISC1 interaction and epigenetic regulation of NMDAR expression and function.