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 Namptmediated 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.