UC San Diego

Spatial memory is susceptible to age-related impairment and relies on intact function of the entorhinal cortex. In this thesis, we examine the hypothesis that normal aging is characterized by structural degeneration of entorhinal neurons, and predict that these changes are reversible through the administration of brain-derived neurotrophic factor (BDNF). In the medial entorhinal cortex, cell filling and spine density analysis of perforant path- projecting neurons revealed that aging results in decreased excitatory input to these neurons. Aged rats exhibited a significant reduction in the density of basilar (18.2%) and apical (16.0%) dendritic spines. Mushroom spines, the most active and stable spine type, exhibited a disproportionate decline with aging. We also found decreased density of the presynaptic marker synaptophysin in the dentate molecular layer of aged rats, suggesting that aged neurons of the medial entorhinal cortex provide fewer inputs to the hippocampus. Age- related changes in neuron structure may be sensitive to brain-derived neurotrophic factor, a protein that influences adult neuron plasticity. To test this hypothesis, we delivered BDNF to the medial entorhinal cortex through lentiviral vector administration. The expression of BDNF, but not NGF or LacZ, reversed the age- related decline in spine density and increased the density of three spine types. Furthermore, the expression of BDNF, but not EGFP, in the entorhinal cortex increased synaptophysin density in the aged rat dentate gyrus. BDNF also influences synaptic function. Based on previous experiments, we predicted that BDNF lentiviral vector delivery to the aged entorhinal cortex would increase long -term potentiation (LTP) in the dentate hilus following tetanic stimulation of the perforant path. On the contrary, we found that chronic BDNF administration significantly reduced hippocampal LTP in comparison with the responses of aged control rats or young subjects. Possible mechanisms are discussed. Collectively, these results indicate that normal aging leads to structural degeneration of perforant path-projecting neurons in the medial entorhinal cortex, and that the changes occur in plastic regions: presynaptic and postsynaptic terminals. Furthermore, lentivirus-mediated BDNF delivery to the entorhinal cortex reverses age-related structural degeneration of entorhinal neurons and modifies the function of perforant path-dentate granule cell synapses