| First Author | Stein LR | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 17 | Pages | 5800-15 |
| PubMed ID | 24760840 | Mgi Jnum | J:210614 |
| Mgi Id | MGI:5571528 | Doi | 10.1523/JNEUROSCI.4730-13.2014 |
| Citation | Stein LR, et al. (2014) Expression of Nampt in hippocampal and cortical excitatory neurons is critical for cognitive function. J Neurosci 34(17):5800-15 |
| abstractText | 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 (CaMKIIalphaNampt(-/-) mice). CaMKIIalphaNampt(-/-) 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. |
