DISRUPTION OF A SINGLE ALLELE OF THE NERVE GROWTH-FACTOR GENE RESULTSIN ATROPHY OF BASAL FOREBRAIN CHOLINERGIC NEURONS AND MEMORY DEFICITS

Administration of nerve growth factor (NGF) to aged or lesioned animal s has been shown to reverse the atrophy of basal forebrain cholinergic neurons and ameliorate behavioral deficits, To examine the importance of endogenous NGF in the survival of basal forebrain cholinergic cell s and in spatial memory, mice bearing a disruption mutation in one all ele of the NGF gene were studied, Heterozygous mutant mice (ngf+/-) ha ve reduced levels of NGF mRNA and protein within the hippocampus and w ere found to display significant deficits in memory acquisition and re tention in the Morris water maze. The behavioral deficits observed in NGF-deficient mice were accompanied by both shrinkage and loss of sept al cells expressing cholinergic markers and by a decrease in cholinerg ic innervation of the hippocampus. Infusions of NGF into the lateral v entricle of adult ngf+/- mice abolished the deficits on the water maze task. Prolonged exposure to NGF may be required to induce cognitive e ffects, because reversal of the acquisition deficit was seen after lon g (5 weeks) but not short (3 d) infusion, Although NGF administration did not result in any improvement in the number of septal cells labele d for choline acetyltransferase, this treatment did effectively correc t the deficits in both size of cholinergic neurons and density of chol inergic innervation of the hippocampus, These findings demonstrate the importance of endogenous NGF for survival and function of basal foreb rain cholinergic neurons and reveal that partial depletion of this tro phic factor is associated with measurable deficits in learning and mem ory.