Enhanced Learning in Mice Parallels Vector-Mediated Nerve Growth Factor Expression in Hippocampus

Spatial learning requires the integrity of the nerve growth factor (NGF)-responsive septohippocampal pathway. Loss of a single NGF allele at the mouse NGF locus (heterozygous null, ngf(+/-)) reduces septohippocampal NGF levels and NGF-regulated cholinergic neurotransmitter enzymes and results in spatial learning deficits in adult animals. A herpes simplex virus (HSV) amplicon vector was utilized to locally deliver NGF to the hippocampus of mice heterozygous and wild type (ngf(+/+)) at the NGF gene locus. NGF gene transfer produced transient increases in NGF protein levels and choline acetyltransferase activity in both ngf(+/-) and ngf(+/+) mice. However, spatial learning capability was improved only in ngf(+/-) mice. In aggregate, these findings suggest that amplicon-directed expression of NGF in subjects with baseline septohippocampal dysfunction can correct spatial learning deficits.