Deletion of Glycogen Synthase Kinase-3β in D 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 D receptor (DR)-mediated signaling to affect dopamine-dependent behaviors. However, the mechanisms underlying the GSK-3β modulation of cognitive function via DRs remains unclear.

METHODS

This study explored how conditional cell-type-specific ablation of GSK-3β in DR+ neurons (DR-GSK-3β) in the brain affects synaptic function in the medial PFC (mPFC). Both male and female (postnatal days 60-90) mice, including 140 DR, 24 DR, 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 DR-GSK-3β mice, along with increased dopamine modulation of NMDAR-mediated current. Consistently, NR2A and NR2B protein levels were elevated in mPFC of DR-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 DR-GSK-3β mice. Indeed, DR-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 DR-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 DR-DISC1 interaction and epigenetic regulation of NMDAR expression and function.