Differential regulation of GluA1 expression by ketamine and memantine.
Evidence from preclinical and clinical studies shows that ketamine, a noncompetitive NMDA receptor antagonist, exerts rapid and sustained antidepressant responses. However, ketamine's psychotomimetic side effects and abuse liability limit the clinical use of the compound. Interestingly, memantine, another NMDA receptor channel blocker, processes no defined antidepressant property but is much safer and clinical tolerated. Understanding why ketamine but not memantine exhibits rapid antidepressant responses is important to elucidate the cellular signaling underlying the fast antidepressant actions of ketamine and to design a new safer generation of fast-acting antidepressants. Here we show that ketamine but memantine caused a rapid and sustained antidepressant-like responses in forced swim test (FST). Both drugs enhanced GluA1 S845 phosphorylation and potentiated Schaffer collateral-CA1 synaptic transmission. However, ketamine but not memantine elevated the expression of GluA1. Incubating acutely prepared hippocampal slices with ketamine but not memantine enhanced mTOR phosphorylation in a time course parallel to the time course of GluA1 elevation. Our results suggest that distinct properties in regulation of mTOR phosphorylation and synaptic protein expression may underlie the differential effectiveness of ketamine and memantine in their antidepressant responses.
Department of Physiology, Southern Illinois University School of Medicine, 1135 Lincoln Drive, Carbondale, IL 62901, USA.
Ke
K
Zhang
Department of Physiology, Southern Illinois University School of Medicine, 1135 Lincoln Drive, Carbondale, IL 62901, USA.
Vitor Nagai
VN
Yamaki
The Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang Road, Guangzhou, Guangdong, 51030, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang Road, Guangzhou, Guangdong 51030, China.
Zhisheng
Z
Wei
The Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang Road, Guangzhou, Guangdong, 51030, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang Road, Guangzhou, Guangdong 51030, China.
Yu
Y
Zheng
Department of Physiology, Southern Illinois University School of Medicine, 1135 Lincoln Drive, Carbondale, IL 62901, USA; Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA. Electronic address: cai001@siu.edu.
Xiang
X
Cai
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects; D066298:In Vitro Techniques; D007649:Ketamine / Q000494:pharmacology* / Q000627:therapeutic use; D008559:Memantine / Q000494:pharmacology*; D010721:Phosphinic Acids / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D013550:Swimming / Q000523:psychology; D009435:Synaptic Transmission / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D001596:Benzylamines; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D007649:Ketamine; D008559:Memantine; D010721:Phosphinic Acids; D010852:Picrotoxin; D018091:Receptors, AMPA; C083008:CGP 52432
AMPA receptor; GluA1 Ser845; Ketamine; Major depressive disorder; Memantine