Regulation of hippocampal long-term potentiation and long-term depression by diacylglycerol kinase ζ.
Diacylglycerol (DAG) is an important signaling molecule at neuronal synapses. Generation of synaptic DAG is triggered by the activation of diverse surface receptors including N-methyl-D-aspartate (NMDA) receptors and metabotropic glutamate receptors. The action of DAG is terminated by enzymatic conversion of DAG to phosphatidic acid (PA) by DAG kinases (DGKs). DGKζ, one of many mammalian DGKs, is localized to synapses through direct interaction with the postsynaptic scaffolding protein PSD-95, and regulates dendritic spine maintenance by promoting DAG-to-PA conversion. However, a role for DGKζ in the regulation of synaptic plasticity has not been explored. We report here that Schaffer collateral-CA1 pyramidal synapses in the hippocampus of DGKζ-knockout (DGKζ(-/-) ) mice show enhanced long-term potentiation (LTP) and attenuated long-term depression (LTD). The attenuated LTD at DGKζ(-/-) synapses involves both NMDA receptors and metabotropic glutamate receptors. These changes in LTP and LTD were reversed by phospholipase C inhibition, which blocks DAG production. Similar reversals in both LTP and LTD were also induced by inhibition of protein kinase C, which acts downstream of DAG. These results suggest that DGKζ regulates hippocampal LTP and LTD by promoting DAG-to-PA conversion, and establish that phospholipase C and protein kinase C lie upstream and downstream, respectively, of DGKζ-dependent regulation of hippocampal LTP and LTD.
Department of Physiology and Dental Research Institute, Seoul National University School of Dentistry, Seoul 110-749, Korea.
Jinsoo
J
Seo
Karam
K
Kim
Seil
S
Jang
Seungnam
S
Han
Se-Young
SY
Choi
Eunjoon
E
Kim
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000201:enzymology / Q000502:physiology*; D049229:Dendritic Spines / Q000201:enzymology; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004963:Estrenes / Q000494:pharmacology; D051528:Guanylate Kinases / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology; D010712:Phosphatidic Acids / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017966:Pyramidal Cells / Q000201:enzymology / Q000502:physiology; D011760:Pyrrolidinones / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
C011439:1,2-diacylglycerol; D004075:Diglycerides; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D004963:Estrenes; D007211:Indoles; D008565:Membrane Proteins; D010712:Phosphatidic Acids; D011760:Pyrrolidinones; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C074854:U 73343; D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse; D011493:Protein Kinase C; D051528:Guanylate Kinases; D010738:Type C Phospholipases; C064758:Ro 31-8220