TY - JOUR T1 - Expression of Nampt in Hippocampal and Cortical Excitatory Neurons Is Critical for Cognitive Function JF - The Journal of Neuroscience JO - J. Neurosci. SP - 5800 LP - 5815 DO - 10.1523/JNEUROSCI.4730-13.2014 VL - 34 IS - 17 AU - Liana Roberts Stein AU - David F. Wozniak AU - Joshua T. Dearborn AU - Shunsuke Kubota AU - Rajendra S. Apte AU - Yukitoshi Izumi AU - Charles F. Zorumski AU - Shin-ichiro Imai Y1 - 2014/04/23 UR - http://www.jneurosci.org/content/34/17/5800.abstract N2 - 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. ER -