Nampt is required for long-term depression and the function of GluN2B subunit-containing NMDA receptors.
Nicotinamide adenine dinucleotide (NAD(+)) is an essential coenzyme/cosubstrate for many biological processes in cellular metabolism. The rate-limiting step in the major pathway of mammalian NAD(+) biosynthesis is mediated by nicotinamide phosphoribosyltransferase (Nampt). Previously, we showed that mice lacking Nampt in forebrain excitatory neurons (CamKIIαNampt(-/-) mice) exhibited hyperactivity, impaired learning and memory, and reduced anxiety-like behaviors. However, it remained unclear if these functional effects were accompanied by synaptic changes. Here, we show that CamKIIαNampt(-/-) mice have impaired induction of long-term depression (LTD) in the Schaffer collateral pathway, but normal induction of long-term potentiation (LTP), at postnatal day 30. Pharmacological assessments demonstrated that CamKIIαNampt(-/-) mice also display dysfunction of synaptic GluN2B (NR2B)-containing N-methyl-d-aspartate receptors (NMDARs) prior to changes in NMDAR subunit expression. These results support a novel, important role for Nampt-mediated NAD(+) biosynthesis in LTD and in the function of GluN2B-containing NMDARs.
Department of Developmental Biology, Washington University School of Medicine, Campus Box 8103, 660 South Euclid Avenue, St. Louis, MO 63110, USA; Department of Psychiatry, The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: LianaLRoberts@gmail.com.
Liana Roberts
LR
Stein
Department of Psychiatry, The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110, USA; Department of Anatomy and Neurobiology, Washington University School of Medicine, Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: zorumskc@wustl.edu.
Charles F
CF
Zorumski
Department of Developmental Biology, Washington University School of Medicine, Campus Box 8103, 660 South Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: imaishin@wustl.edu.
Shin-Ichiro
S
Imai
Department of Psychiatry, The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: izumiy@wustl.edu.
Yukitoshi
Y
Izumi
D000375:Aging / Q000187:drug effects / Q000502:physiology; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D017774:Long-Term Potentiation / Q000187:drug effects; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018345:Mice, Knockout; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism*; D016548:Prosencephalon / Q000187:drug effects / Q000201:enzymology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D046509:Tissue Culture Techniques
D016207:Cytokines; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse
GluN2B; Long-term depression; N-methyl-d-aspartate receptor; NAD(+); NR2B; Nampt