F3/contactin is a cell-adhesion molecule involved in synapse building, maintenance and functioning. It is expressed in developing hippocampus, progressively increasing during postnatal life but decreasing with aging. We have previously shown that hippocampal overexpression of F3/contactin promotes adult neurogenesis and improves synaptic plasticity and memory. Here we aimed to investigate whether F3/contactin might counteract the cognitive decline in aged mice.We used TAG/ F3 transgenic mice, where F3/contactin overexpression was induced under control of regulatory sequences from the human TAG-1 (TAX-1) gene. Tg and wild type mice aged 20-24 month-old were compared to 5 month-old wild type animals. Electrophysiological studies were performed to explore hippocampal synaptic plasticity (long-term potentiation, LTP, at CA1 area), whereas behavioral test such as Morris Water Maze and Novel Object Recognition allowed as to investigate spatial and recognition memory. We also evaluated the expression of pro- and anti-apoptotic molecules (Caspase-3, Bax, Bcl-2, BDNF and CREB) as well as amyloid precursor protein (APP) processing toward amyloid-beta (Aβ) production. Old TAG/F3 homozygous mice presented an improvement of LTP and memory compared with aged wild type littermates. Moreover, they showed an increase of the pro-apoptotic molecules Caspase-3 and Bax, and a concomitant increase of the anti-apoptotic and plasticity-related pathway BDNF/CREB/Bcl-2. Finally, APP processing was shifted toward sAPPα with a consequent decrease of sAPPβ and Aβ levels. Our data suggest that F3/contactin plays a role in hippocampal synaptic plasticity and memory in old mice, probably by acting on molecular pathways related to apoptosis and Aβ production. These findings might be relevant for new therapeutical approaches against the impairment of learning and memory during aging.
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