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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]

Brain cholesterol metabolic products include neurosteroids and oxysterols, which play important roles in cellular physiology. In neurons, the cholesterol oxidation product, 24S-hydroxycholesterol (24S-HC), is a regulator of signaling and transcription. Here, we examined the behavioral effects of 24S-HC loss, using global and cell-selective genetic deletion of the synthetic enzyme CYP46A1. Mice that are globally deficient in CYP46A1 exhibited hypoactivity at young ages and unexpected increases in conditioned fear memory. Despite strong reductions in hippocampal 24S-HC in mice with selective loss of CYP46A1 in VGLUT1-positive cells, behavioral effects were not recapitulated in these conditional knockout mice. Global knockout produced strong, developmentally dependent transcriptional effects on select cholesterol metabolism genes. These included paradoxical changes in Liver X Receptor targets. Again, conditional knockout was insufficient to recapitulate most changes. Overall, our results highlight the complex effects of 24S-HC in an in vivo setting that are not fully predicted by known mechanisms. The results also demonstrate that the complete inhibition of enzymatic activity may be needed for a detectable, therapeutically relevant impact on gene expression and behavior. [ABSTRACT FROM AUTHOR]

Abstract: Previously, we identified separate genetic influences on ventral versus dorsal hippocampal volume in BXD recombinant inbred mice [Martin MV, Dong HX, Vallera D, Lu L, Williams RW, Rosen GD, et al. Independent quantitative trait loci influence ventral and dorsal hippocampal volume in recombinant inbred strains of mice. Genes Brain Behav 2006;5:614–23]. Based on genotype at genetic markers associated with ventral hippocampal volume, we evaluated BXD mouse strains with relatively small versus large ventral hippocampal volumes using numerous behavioral paradigms known to rely upon hippocampal function and several other tasks that tap into behaviors analogous to those often impaired in schizophrenia. We observed a relationship between genotype at markers known to influence ventral hippocampal volume and working memory at an intermediate memory load. There was no association between genotype at markers known to influence ventral hippocampal volume and spatial reference memory, prepulse inhibition, or elevated plus maze performance. The relevance of these findings for understanding the pathophysiology of schizophrenia are discussed, including the possibility that genetic predisposition toward anterior hippocampal volume reductions and working memory deficits in schizophrenia may be related through a shared genetic locus. [Copyright &y& Elsevier]