1. Expression of Nampt in Hippocampal and Cortical Excitatory Neurons Is Critical for Cognitive Function.
- Author
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Stein, Liana Roberts, Wozniak, David F., Dearborn, Joshua T., Shunsuke Kubota, Apte, Rajendra S., Yukitoshi Izumi, Zorumski, Charles F., and Shin-ichiro Imai
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HIPPOCAMPUS (Brain) , *NAD (Coenzyme) , *NICOTINAMIDE , *NEURONS , *PHOSPHORIBOSYLTRANSFERASES , *CEREBRAL atrophy - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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