Expression of Nampt in hippocampal and cortical excitatory neurons is critical for cognitive function.
Nicotinamide adenine dinucleotide (NAD(+)) is an enzyme cofactor or cosubstrate in many essential biological pathways. To date, the primary source of neuronal NAD(+) has been unclear. NAD(+) can be synthesized from several different precursors, among which nicotinamide is the substrate predominantly used in mammals. The rate-limiting step in the NAD(+) biosynthetic pathway from nicotinamide is performed by nicotinamide phosphoribosyltransferase (Nampt). Here, we tested the hypothesis that neurons use intracellular Nampt-mediated NAD(+) biosynthesis by generating and evaluating mice lacking Nampt in forebrain excitatory neurons (CaMKIIαNampt(-/-) mice). CaMKIIαNampt(-/-) mice showed hippocampal and cortical atrophy, astrogliosis, microgliosis, and abnormal CA1 dendritic morphology by 2-3 months of age. Importantly, these histological changes occurred with altered intrahippocampal connectivity and abnormal behavior; including hyperactivity, some defects in motor skills, memory impairment, and reduced anxiety, but in the absence of impaired sensory processes or long-term potentiation of the Schaffer collateral pathway. These results clearly demonstrate that forebrain excitatory neurons mainly use intracellular Nampt-mediated NAD(+) biosynthesis to mediate their survival and function. Studying this particular NAD(+) biosynthetic pathway in these neurons provides critical insight into their vulnerability to pathophysiological stimuli and the development of therapeutic and preventive interventions for their preservation.
Department of Developmental Biology, Department of Psychiatry, The Taylor Family Institute for Innovative Psychiatric Research, Department of Ophthalmology, and Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110.
Liana Roberts
LR
Stein
David F
DF
Wozniak
Joshua T
JT
Dearborn
Shunsuke
S
Kubota
Rajendra S
RS
Apte
Yukitoshi
Y
Izumi
Charles F
CF
Zorumski
Shin-ichiro
S
Imai
D000818:Animals; D001284:Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D003071:Cognition / Q000502:physiology*; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008568:Memory / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009415:Nerve Net / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism*
D054409:Nicotinamide Phosphoribosyltransferase
CA1; NAD+; Nampt; cognition; hippocampus