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

• CamKIIαNampt−/− mice lack the NAD+ biosynthetic enzyme Nampt in forebrain neurons.
• CamKIIαNampt−/− mice have impaired induction of long-term depression (LTD).
• CamKIIαNampt−/− mice have normal induction of long-term potentiation (LTP).
• CamKIIαNampt−/− mice have dysfunctional GluN2B-containing NMDARs.
• Nampt plays a critical, novel role in LTD and GluN2B-containing NMDAR function.

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.