Glial cell line-derived neurotrophic factor (GDNF) was assayed for its neurotrophic effects against the neuronal atrophy that causes cognitive deficits in old age. Aged Fisher 344 rats with impairment in the Morris water maze received intrahippocampal injections at the dorsal CA1 area of either a lentiviral vector encoding human GDNF or the same vector encoding human green fluorescent protein as a control. Recombinant lentiviral vectors constructed with human cytomegalovirus promotor and pseudotyped with lyssavirus Mokola glycoprotein specifically transduced the astrocytes in vivo. Astrocyte-secreted GDNF enhanced neuron function as shown by local increases in synthesis of the neurotransmitters acetylcholine, dopamine and serotonin. This neurotrophic effect led to cognitive improvement of the rats as early as 2 weeks after gene transduction. Spatial learning and memory testing showed a significant gain in cognitive abilities due to GDNF exposure, whereas control-transduced rats kept their performance at the chance level. These results confirm the broad spectrum of the neurotrophic action of GDNF and open new gene therapy possibilities for reducing age-related neurodegeneration.