Phenotypic knockout of nerve growth factor in adult transgenic mice reveals severe deficits in basal forebrain cholinergic neurons, cell death in thespleen, and skeletal muscle dystrophy

The disruption of the nerve growth factor (NGF) gene in transgenic mice lea ds to a lethal phenotype (Crowley et al., 1994) and hinders the study of NG F functions in the adult. In this study the phenotypic knockout of NGF in a dult mice was achieved by expressing transgenic anti-NGF antibodies, under the control of the human cytomegalovirus promoter. In adult mice, antibody levels are 2000-fold higher than in newborns. Classical NGF targets, includ ing sympathetic and sensory neurons, are severely affected. In the CNS, bas al forebrain and hippocampal cholinergic neurons are not affected in the ea rly postnatal period, whereas they are greatly reduced in the adult (55 and 62% reduction, respectively). Adult mice show a reduced ability in spatial learning behavioral tasks. Adult, but not neonatal, transgenic mice furthe r show a new phenotype at the level of peripheral tissues, such as apoptosi s in the spleen and dystrophy of skeletal muscles. The analysis of this nov el comprehensive transgenic model settles the controversial issue regarding the NGF dependence of cholinergic neurons in adult animals and reveals new NGF functions in adult non-neuronal tissues. The results demonstrate that the decreased availability of NGF in the adult causes phenotypic effects vi a processes that are at least partially distinct from early developmental e ffects of NGF deprivation.