In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 34, No. 17 ( 2014-04-23), p. 5800-5815
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 ( CaMKII α Nampt −/− mice). CaMKII α Nampt −/− 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.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.4730-13.2014
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2014
detail.hit.zdb_id:
1475274-8
SSG:
12
