The cell adhesion molecule F3/contactin improves synaptic plasticity and memory in aged mice.

OBJECTIVES: 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 at investigating whether F3/contactin might counteract the cognitive decline in aged mice. MATERIALS AND METHODS: We used TAG/F3 transgenic mice, where F3/contactin overexpression is induced under control of regulatory sequences from the human TAG-1 (TAX-1) gene. TAG/F3 and wild type mice aged 20-24 months 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 (Morris Water Maze and Novel Object Recognition) allowed us 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 (Abeta) production. RESULTS: Old TAG/F3 underwent improved LTP and memory compared to age-matched wild type mice. Moreover, they showed increased expression of 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 sAPPalpha with a consequent decrease of sAPPbeta and Abeta levels. CONCLUSIONS: 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 Abeta production. These findings might be relevant for devising new therapeutical approaches against the impairment of learning and memory during aging.