Remission of social behavior impairment by oral administration of a precursor of NAD in CD157, but not in CD38, knockout mice

Abstract

Nicotinamide adenine dinucleotide (NAD) is a substrate of adenosine diphosphate (ADP)-ribosyl cyclase and is catalyzed to cyclic ADP-ribose (cADPR) by CD38 and/or CD157. cADPR, a Ca²⁺ mobilizing second messenger, is critical in releasing oxytocin from the hypothalamus into the brain. Although NAD precursors effectively play a role in neurodegenerative disorders, muscular dystrophy, and senescence, the beneficial effects of elevating NAD by NAD precursor supplementation on brain function, especially social interaction, and whether CD38 is required in this response, has not been intensely studied. Here, we report that oral gavage administration of nicotinamide riboside, a perspective NAD precursor with high bioavailability, for 12 days did not show any suppressive or increasing effects on sociability (mouse's interest in social targets compared to non-social targets) in both CD157KO and CD38KO male mice models in a three-chamber test. CD157KO and CD38KO mice displayed no social preference (that is, more interest towards a novel mouse than a familiar one) behavior. This defect was rescued after oral gavage administration of nicotinamide riboside for 12 days in CD157KO mice, but not in CD38KO mice. Social memory was not observed in CD157KO and CD38KO mice; subsequently, nicotinamide riboside administration had no effect on social memory. Together with the results that nicotinamide riboside had essentially no or little effect on body weight during treatment in CD157KO mice, nicotinamide riboside is less harmful and has beneficial effect on defects in recovery from social behavioral, for which CD38 is required in mice.

Keywords: CD157; CD38; NAD; neuromodulator; nicotinamide riboside; social behavior.

Figure 1

Nicotinamide riboside (NR) treatment has no effect on mouse body weight. (A) Body weight of C57BL6 male mice, before (0 day) and after NR (13 mg/mouse) or placebo (PL) treatment for 12 days (PL: n = 6, unpaired t-test, t(10) = 0.3571, P = 0.7285; NR: n = 6, t(10) = 1.598, P = 0.1412). (B) Body weight of CD157 KO mice before (0 day) and after NR or placebo (PL) treatment for 12 days (PL: n = 6, unpaired t-test, t(10) = 0.2399, P = 0.8152; NR: n = 6, unpaired t-test, t(10) = 0.4341, P = 0.6734).

Figure 2

Nicotinamide riboside (NR) treatment has no apparent effect on sociability in C57BL6 (BL6) and CD157KO male mice in the three-chamber test. Duration spent in the chamber with Stranger 1 mouse in a cage (Str1) or a non-social target (object) by wild-type (BL6; A) or CD157KO (B) mice. (C, D) Duration spent in the chamber with Stranger 1 mouse in a cage (Str1) or a non-social target (object) by wild-type (BL6; C) or CD157KO (D) mice, which were treated with gavage administration of saline (PL) or nicotinamide riboside (NR) for 12 days and then examined. Two-tailed Student’s t-test, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Figure 3

Nicotinamide riboside (NR) treatment corrects social preference deficit in CD157KO mice. Duration spent in the chamber with the familiar mouse in a cage (Str1) or a novel mouse (Str2) by wild-type (BL6; A, C) or CD157KO (B, D) mice. Mice were treated with gavage administration of saline (PL) or nicotinamide riboside (NR) for 12 days (C, D) or were without any treatment (A, B). Two-tailed Student’s t-test, *P < 0.05, **P < 0.01. ns, not significant.

Figure 4

Wild-type C57BL6 (BL6) and C157KO mice show absence of social memory and no or little effect of nicotinamide riboside (NR) treatment. Duration spent in the chamber with the familiar mouse in a cage (Str1) or a novel mouse (Str3) by wild-type (BL6; A, C) or CD157KO (B, D) mice. Mice were treated with gavage administration of saline (PL) or NR for 12 days (C, D) or were without any treatment (A, B).

Figure 5

Nicotinamide riboside (NR) treatment has no apparent effect on sociability in wild-type (ICR) and CD38KO male mice in the three-chamber test. Duration spent in the chamber with a novel mouse in a cage (Str1) or a non-social target (object) by ICR (A, C) or CD38KO (B, D) mice. Mice were treated with gavage administration of saline (PL) or NR for 12 days (C, D) or were without any treatment (A, B), and then were examined for sociability behavior. Two-tailed Student’s t-test, ****P < 0.0001.

Figure 6

Effects of nicotinamide riboside (NR) or saline (PL) treatment on social preference behavior in wild-type (ICR) or CD38KO mice. Duration spent in the chamber with the familiar mouse in a cage (Str1) or a novel mouse (Str2) by wild-type (A, C) or CD38KO (B, D) male mice. Mice were treated with gavage administration of saline (PL) or NR for 12 days (C, D) or were without any treatment (A, B). Two-tailed Student’s t-test, **P < 0.01, ****P < 0.0001. ns, not significant.

Figure 7

Social memory behavior in wild-type (ICR) and CD38KO mice and no or little effect of nicotinamide riboside (NR) treatment. Duration spent in the chamber with the familiar mouse in a cage (Str1) or a novel mouse (Str3) by ICR (A, C) or CD38KO (B, D) mice. Mice were treated with gavage administration of saline (PL) or NR for 12 days (C, D) or were without any treatment (A, B). Note that social memory behavior was observed in ICR mice (A, C) but was not affected by NR treatment (C). Two-tailed Student’s t-test, *P < 0.05.

Figure 8

A simplified scheme for possible NAD catabolism from nicotinamide riboside (NR) and metabolism from NAD to cyclic ADP-ribose (cADPR) in wild-type (WT), CD38KO, and CD157KO mice. This is a reciprocal pathway from NR supplementation to NAD and nicotinamide (Nam) via nicotinamide mononucleotide (NMN) catalyzed by CD157, CD73 nicotinamide riboside kinases (NRKs), CD38, and nicotinamide mononucleotide adenylyl transferase (NMNATs); NAD is metabolized to Nam, ADP-ribose (ADPR), and cADPR. cADPR production is greatly reduced in CD38KO mice, but less affected in CD157KO mice, which induces different levels of oxytocin release. Social behaviors consist of sociability, social preference, and social memory. Different levels of oxytocin release elicit different levels of impairment of three subclasses of social behaviors. Note that impaired social preference is recovered in CD157KO, but not in CD38KO mice. It is noted that NAD concentration increase in the brain after nicotinamide riboside was confirmed in CD157KO mice (17), but not examined in CD38KO supplemented with nicotinamide riboside.