Vagus nerve stimulation increases neurotrophins gene expression and alters cell proliferation in the rat hippocampus

Vagus nerve stimulation (VNS) is effective in patients with treatment-resistant epilepsy. More recently, VNS has been ap- proved for treatment-resistant depression; nevertheless, the molec- ular mechanism(s) underlying its therapeutic action remains un- clear. In light of the proven anticonvulsant properties of VNS, its modulation of neurochemical systems implicated in major de- pression and impact on neuronal functional activity and plasticity, we tested the possibility that VNS could promote the synthesis of neurotrophic factors (BDNF, bFGF and NGF) that promote survival, maintenance and proliferation of neuronal cells, in the rat brain. Moreover, we investigate whether VNS could interfere with neurogenesis in the hippocampal dentate gyrus. RNase protection assay revealed that acute VNS increases the abundance of BDNF and bFGF mRNAs in the hippocampus, and do not significantly alters the abundance of NGF mRNA. Immunohistochemical studies demonstrate that VNS alters cell proliferation and neurogenesis in dentate gyrus, as demonstrated by the double labeling with specific antibodies for the nuclear neuronal protein NeuN and BrdU. Our results suggest that VNS could trigger neuronal plastic changes and demonstrate that such stimulation induced an increase in the gene expression of BDNF and bFGF in the rat hippocampus. These increases in growth factors were associated with a disrup- tion of cell proliferation and neurogenesis process in the granule cell layer of the dentate gyrus. These new findings contribute to elucidate the molecular mechanisms underlying the action of VNS, a new therapeutic tool for the treatment of epilepsy and depression. References S.07.04 [1] [2] [3] Marrosu, F., Santoni, F., Puligheddu, M., Barberini, L., Maleci, A., Ennas, F., Mascia, M., Zanetti, G., Tuveri, A., Biggio G., 2005. Increase in 20−50 Hz (gamma frequencies) power spectrum and synchronization after chronic vagal nerve stimulation. Clin Neurophysiol 116, 2026−36. Marrosu, F., Serra, A., Maleci, A., Pulicheddu, M., Biggio, G., Piga., M., 2003. Correlation between GABAA receptor density and va- gus nerve stimulation in individuals with drug-resistant partial epilepsy. Epilepsy Res 55, 59−70. Palma, E., Torchia, G., Limatola, C., Trettel, A., Arcella, A., Can- tore, G., Di Gennaro, G., Manfredi, M., Esposito, V., Quarato, P.P., Miledi, R., Eusebi, F., 2005. BDNF modulates GABAA receptors microtransplated from thehuman epileptic brain to Xenopus oocites. Proc Natl Acad Sci USA 102, 1667–1672.