Nicotinamide riboside supplementation corrects deficits in oxytocin, sociability and anxiety of CD157 mutants in a mouse model of autism spectrum disorder

Maria Gerasimenko,Kazumi Furuhara,Chiharu Tsuji,Stanislav M Cherepanov,Olga Lopatina,Haruhiro Higashida,Shigeru Yokoyama,Charles Brenner,Anna A Shabalova,Alla B Salmina,Katsuhiko Ishihara

doi:10.1038/s41598-019-57236-7

Abstract

Oxytocin (OT) is a critical molecule for social recognition and memory that mediates social and emotional behaviours. In addition, OT acts as an anxiolytic factor and is released during stress. Based on the activity of CD38 as an enzyme that produces the calcium-mobilizing second messenger cyclic ADP-ribose (cADPR), CD157, a sister protein of CD38, has been considered a candidate mediator for the production and release of OT and its social engagement and anti-anxiety functions. However, the limited expression of CD157 in the adult mouse brain undermined confidence that CD157 is an authentic and/or actionable molecular participant in OT-dependent social behaviour. Here, we show that CD157 knockout mice have low levels of circulating OT in cerebrospinal fluid, which can be corrected by the oral administration of nicotinamide riboside, a recently discovered vitamin precursor of nicotinamide adenine dinucleotide (NAD). NAD is the substrate for the CD157- and CD38-dependent production of cADPR. Nicotinamide riboside corrects social deficits and fearful and anxiety-like behaviours in CD157 knockout males. These results suggest that elevating NAD levels with nicotinamide riboside may allow animals with cADPR- and OT-forming deficits to overcome these deficits and function more normally.

Highlights

Oxytocin (OT) plays a role in social recognition, behaviour, and memory through a positive feedback system involving OT-induced OT release in the brain[1,2,3]
Whereas nicotinic acid and tryptophan-dependent synthesis or tissue-restricted, all cells appear to synthesize nicotinamide phosphoribosyltransferase, and nicotinamide riboside kinase (NMRK)[1], which confer the ability to utilize nicotinamide and NR, respectively[17] In a number of conditions of metabolic stress, including heart failure[19], noise-induced hearing loss[20], central brain injury[21] and peripheral neurodegeneration[22], key metabolites such as nicotinamide adenine dinucleotide (NAD)+ and/or NADPH23 are under attack
The results demonstrated that the daily oral administration of NR rescued the social behavioural impairments observed in male CD157KO mice

Summary

Introduction

Oxytocin (OT) plays a role in social recognition, behaviour, and memory through a positive feedback system involving OT-induced OT release in the brain[1,2,3]. CADPR triggers an increase in intracellular free Ca2+ concentrations and, subsequently, Ca2+-dependent OT release from oxytocinergic neurons[10] When this signalling cascade was blocked in CD38 knockout (CD38KO) mice, social memory and recognition and parental nurturing behaviours were disrupted, mainly due to reduced OT secretion[11,12]. Whereas nicotinic acid and tryptophan-dependent synthesis or tissue-restricted, all cells appear to synthesize nicotinamide phosphoribosyltransferase, and nicotinamide riboside kinase (NMRK)[1], which confer the ability to utilize nicotinamide and NR, respectively[17] In a number of conditions of metabolic stress, including heart failure[19], noise-induced hearing loss[20], central brain injury[21] and peripheral neurodegeneration[22], key metabolites such as NAD+ and/or NADPH23 are under attack. We show that biochemical and behavioural defecits of CD157KO mice are reversed by oral administration of NR

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Conclusion