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Deletion of Glycogen Synthase Kinase-3β in D 2 Receptor-Positive Neurons Ameliorates Cognitive Impairment via NMDA Receptor-Dependent Synaptic Plasticity
Journal article   Open access   Peer reviewed

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

Yan-Chun Li, Priyalakshmi Panikker, Bo Xing, Sha-Sha Yang, Cassandra Alexandropoulos, Erin P McEachern, Rita Akumuo, Elise Zhao, Yelena Gulchina, Mikhail V Pletnikov, …
Biological psychiatry (1969), v 87(8), pp 745-755
15 Apr 2020
DOI: https://doi.org/10.1016/j.biopsych.2019.10.025
PMID: 31892408
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103512View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Animals Cognitive Dysfunction Epigenesis, Genetic Female Glycogen Synthase Kinase 3 beta - genetics Male Mice Nerve Tissue Proteins Neuronal Plasticity Prefrontal Cortex - metabolism Receptors, Dopamine D2 - genetics Receptors, Dopamine D2 - metabolism Receptors, N-Methyl-D-Aspartate - genetics Receptors, N-Methyl-D-Aspartate - metabolism
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 (D R)-mediated signaling to affect dopamine-dependent behaviors. However, the mechanisms underlying the GSK-3β modulation of cognitive function via D Rs remains unclear. This study explored how conditional cell-type-specific ablation of GSK-3β in D R+ neurons (D R-GSK-3β ) in the brain affects synaptic function in the medial PFC (mPFC). Both male and female (postnatal days 60-90) mice, including 140 D R, 24 D R, and 38 DISC1 mice, were used. This study found that NMDA receptor (NMDAR) function was significantly increased in layer V pyramidal neurons in mPFC of D R-GSK-3β mice, along with increased dopamine modulation of NMDAR-mediated current. Consistently, NR2A and NR2B protein levels were elevated in mPFC of D R-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 D R-GSK-3β mice. Indeed, D R-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 D R-DISC1 complex was able to reverse the mutant DISC1-induced decrease of NMDAR-mediated currents in the mPFC. This study demonstrates that GSK-3β modulates cognition via D R-DISC1 interaction and epigenetic regulation of NMDAR expression and function.

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Collaboration types
Domestic collaboration
Web of Science research areas
Neurosciences
Psychiatry
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