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

Abstract

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.

Interactions between Intestinal Homeostasis and NAD+ Biology in Regulating Incretin Production and Postprandial Glucose Metabolism

“…Projection neuron-specific NKO mice develop synaptic dysfunction at neuromuscular junctions in the cerebral cortex and motor neuron degeneration-associated muscle atrophy, resulting in death within an average of 22 days [ 70 ]. The cortex- and hippocampus-specific NKO mice exhibit cortical and hippocampal atrophy, abnormal neuronal morphology, and impaired memory and cognitive function [ 66 , 71 ]. Moreover, the hippocampal CA1 region-specific NKO impairs cognitive function [ 72 ], and rod and cone cell-specific NKO mice exhibit mitochondrial dysfunction and severe retinal degeneration [ 73 ].…”

CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves

“…Our previous studies have demonstrated that NAMPT in forebrain excitatory neurons is critical for cognitive and behavioral functions. 17 , 20 In these studies, we used mice lacking Nampt in forebrain excitatory neurons ( CaMKIIαNampt −/− mice). Although these mice exhibit remarkable phenotypes that demonstrate the importance of NAMPT in hippocampal cognitive functions, it is difficult to know whether NAMPT-mediated NAD + biosynthesis indeed contributes to age-associated changes in hippocampal cognitive functions.…”

Safety and efficacy of long-term nicotinamide mononucleotide supplementation on metabolism, sleep, and nicotinamide adenine dinucleotide biosynthesis in healthy, middle-aged Japanese men

“…It has become a consensus that the systemic decrease in NAD + levels is a driving force for some age-associated pathophysiologies [5,11,14,15]. NAD + levels decrease with aging and obesity in many tissues and organs in both rodents [16][17][18][19][20][21][22][23][24][25] and humans [22,[26][27][28], causing obesity-and aging-related complications, including postprandial hyperglycemia [16,29,30], insulin resistance [6,31,32], impaired energy metabolism [33], muscle atrophy [20], and impaired memory/ cognition [34][35][36] in rodents. These findings provide a scientific rationale for augmenting NAD + biosynthesis as a preventive and therapeutic strategy for obese and/or elderly individuals.…”