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Hyperdopaminergic modulation of inhibitory transmission is dependent on GSK-3β signaling-mediated trafficking of GABAA receptors
Journal article   Open access   Peer reviewed

Hyperdopaminergic modulation of inhibitory transmission is dependent on GSK-3β signaling-mediated trafficking of GABAA receptors

Yan-Chun Li, Min-Juan Wang and Wen-Jun Gao
Journal of neurochemistry, v 122(2)
Jul 2012
DOI: https://doi.org/10.1111/j.1471-4159.2012.07790.x
PMID: 22676038
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1111/j.1471-4159.2012.07790.xView
Published, Version of Record (VoR) Open

Abstract

Cross-Linking Reagents Glycogen Synthase Kinase 3 - physiology Guanine Nucleotide Exchange Factors - physiology Synaptic Transmission - physiology Cells, Cultured Rats Glycogen Synthase Kinase 3 beta Prefrontal Cortex - cytology Excitatory Postsynaptic Potentials - drug effects Rats, Sprague-Dawley Dose-Response Relationship, Drug Patch-Clamp Techniques Animals Prefrontal Cortex - drug effects Dynamins - physiology Dopamine - physiology Receptors, Dopamine D2 - drug effects Receptors, GABA-A - physiology Signal Transduction - physiology Synaptic Transmission - drug effects Electrophysiological Phenomena Inositol 1,4,5-Trisphosphate - metabolism Receptors, GABA-A - biosynthesis
Cortical dopamine (DA) modulation of the gamma-amino butyric acid (GABA) system is closely associated with cognitive function and psychiatric disorders. We recently reported that the glycogen synthase kinase 3β (GSK-3β) pathway is required for hyperdopamine/D2 receptor-mediated inhibition of NMDA receptors in the prefrontal cortex. Here we explore whether or not GSK-3β is also involved in dopaminergic modulation of GABAA receptor-mediated inhibitory transmission. We confirmed that DA induces a dose-dependent, bidirectional regulatory effect on inhibitory postsynaptic currents (IPSCs) in prefrontal neurons. The modulatory effects of DA were differentially affected by co-application of GSK-3β inhibitors and different doses of DA. GSK-3β inhibitors completely blocked high-dose (20 μM) DA-induced depressive effects on IPSCs but exhibited limited effects on the facilitating regulation of IPSC in low-dose DA (200 nM). We also confirmed that surface expressions of GABAA receptor β2/3 subunits were significantly decreased by DA applied in cultured prefrontal neurons and in vivo administration of DA reuptake inhibitor. These effects were blocked by prior administration of GSK-3β inhibitors. We explored DA-mediated regulation of GABAA receptor trafficking and exhibited the participation of brefeldin A-inhibited GDP/GTP exchange factor 2 (BIG2) or dynamin-dependent trafficking of GABAA receptors. Together, these data suggest that DA may act through different signaling pathways to affect synaptic inhibition, depending on the concentration. The GSK-3β signaling pathway is involved in DA-induced decrease in BIG2-dependent insertion and an increase in the dynamin-dependent internalization of GABAA receptors, which results in suppression of inhibitory synaptic transmission.

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Web of Science research areas
Biochemistry & Molecular Biology
Neurosciences
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