Galanin is a 29 amino acid neuropeptide, which initiates its biological effects through specific G-protein linked receptors. It has been demonstrated that exogenous galanin or the previously described high-affinity galanin receptor 2 (GALR2)-specific agonist, reduced cell death when co-administered with glutamate or staurosporine, in both wildtype and mutant cultures and that the neuroprotective role played by galanin in the adult hippocampus is mediated at least in part by GALR2 activation (1). In addition it has been shown that adult sensory neurons are dependent, in part, on galanin for neurite extension and that this crucial physiological process is mediated by activation of the GalR2 receptor in a protein kinase C (PKC)-dependent manner (2). This study therefore aimed to investigate whether this survival role involved signalling by activation of PKC which in turn activates the ERK cascade. Here we report that these actions are mediated by activation of the extracellular signal-regulated kinases (ERK) and protein kinase B (Akt). Further, glutamate-induced rise in activated Akt was reduced in mutant organotypic cultures at 10 and 30 min (255% of control value followed by 249% increase relative to WT control at 30 min, n=3) compared with wildtype controls (320% of control value followed by a further increase of 270% increase relative to WT control, n=3) whilst ERK activation was secondarily increased, while in transgenics overexpressing galanin, Akt and ERK were markedly higher than in WT. These results imply that a GALR2-specific agonist might have therapeutic uses in some forms of brain injury.