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© 2014, Springer Science+Business Media New York. The Fas receptor (FasR)/Fas ligand (FasL) system plays a significant role in the process of neuronal loss in neurological disorders. Thus, in the present study, we used a real-time PCR array focused apoptosis (Mouse Apoptosis RT 2 PCR Array) to study the role of the Fas pathway in the apoptotic process that occurs in a kainic acid (KA) mice experimental model. In fact, significant changes in the transcriptional activity of a total of 23 genes were found in the hippocampus of wild-type C57BL/6 mice after 12 h of KA treatment compared to untreated mice. Among the up-regulated genes, we found key factors involved in the extrinsic apoptotic pathway, such as tnf, fas and fasL, and also in caspase genes (caspase-4, caspase-8 and caspase-3). To discern the importance of the FasR/FasL pathway, mice lacking the functional Fas death receptor (lpr) were also treated with KA. After 24 h of neurotoxin treatment, lpr mice exhibited a reduced number of apoptotic positive cells, determined by the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) method in different regions of the hippocampus, when compared to wild-type mice. In addition, treatment of lpr mice with KA did not produce significant changes in the transcriptional activity of genes related to apoptosis in the hippocampus, either in the fas and fas ligand genes or in caspase-4 and caspase-8 and the executioner caspase-3 genes, as occurred in wild-type C57BL/6 mice. Thus, these data provide direct evidence that Fas signalling plays a key role in the induction of apoptosis in the hippocampus following KA treatment, making the inhibition of the death receptor pathway a potentially suitable target for excitotoxicity neuroprotection in neurological conditions such as epilepsy. ; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CiberNed-Instituto de Salud Carlos III) and by grants fromMinisterio de Ciencia (MICINN, MINECO) SAF2009-08233 and SAF2012-34177 and Fundación Ramón Areces to JJL. Grant 2009/SGR00853 from the Generalitat de Catalunya (Autonomous Government of Catalonia) and grants BFU2010-19119/BFI to CA, SAF2011-23631 to AC, and SAF2012-39852-C02-01 to MP from the Spanish Ministerio de Ciencia (MICINN, MINECO) also supported the study. Grant 0177594 from CONACYT (Mexico) ; Peer Reviewed