Hyperdopaminergic modulation of inhibitory transmission is dependent on GSK-3β signaling-mediated trafficking of GABAA receptors.
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.
Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
Yan-Chun
YC
Li
Min-Juan
MJ
Wang
Wen-Jun
WJ
Gao
D000818:Animals; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D034281:Dynamins / Q000502:physiology; D055724:Electrophysiological Phenomena; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
C488152:Arfgef2 protein, rat; D003432:Cross-Linking Reagents; D020662:Guanine Nucleotide Exchange Factors; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D015544:Inositol 1,4,5-Trisphosphate; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D034281:Dynamins; D004298:Dopamine