Nampt is required for long-term depression and the function of GluN2B subunit-containing NMDA receptors

Nicotinamide adenine dinucleotide (HAD) 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 (CamKII alpha Nampt(-/-) 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 CamKII alpha Nampt(-/-) 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 CamKII alpha Nampt(-/-) 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. (C) 2015 Elsevier Inc. All rights reserved.