Neuronal phenotype characterization of faim-ko mice

Resumen

Fas apoptotic inhibitory molecule 1 (FAIM1) gene is highly conserved in the evolution and was firstly characterized in B cells in 1999. FAIM1 codifies for at least four isoforms, among which FAIM-L and FAIM-S are the most relevant. FAIM-L is formed by alternative splicing, is exclusively expressed in neurons and contains twenty-two amino acids more than the first isoform characterized in B cells, FAIM-S. The first described role of FAIM1 was this protective effect against death-receptor mediated cell death. FAIM-S and FAIM-L exert this function in different cells, and FAIM-L is the only FAIM1 isoform that protects neurons against induced apoptosis. Recently, a protective role of FAIM1 in cellular stress-induced cell death has been reported. FAIM1 have been also implicated in non-apoptotic functions. FAIM-S participates in different non-apoptotic functions in the immune system, in glucose and lipid metabolism, in protein aggregation and in neurite outgrowth. Otherwise, FAIM-L acts as a regulator in synaptic transmission, axonal degeneration and synaptic plasticity process of long-term depression. Besides, FAIM1 isoforms have relevant roles in different diseases. In that sense, FAIM-S is deregulated in multiple myeloma and obesity and FAIM-L is downregulated in Alzheimer’s disease. Although some FAIM1 isoforms functions have been reported in nervous system, many questions about their actions in CNS are still a high exciting mystery. Therefore, we decided to characterize the neuronal phenotype of FAIM-KO mice to unravel FAIM1 functions in brain. Surprisingly, we observed age-dependent sensory-induced seizures in FAIM-KO mice. Owing to that finding, the work was focused to unravel mechanisms related with seizure susceptibility in FAIM-KO mice. FAIM-KO mice with seizure showed typical hippocampal cellular and molecular alterations reported in epilepsy models such ectopic neuropeptide Y expression, increase neurogenesis and increase c-fos expression in hippocampus. However, these effects have not been observed in non-convulsive FAIM-KO mice. Although, neuroinflammation and cell death were not apparent in FAIM-KO mice, these animals exhibit a decrease in glial density in hippocampus and alterations in parvalbumin- and calretinin-containing interneuron populations. These mice also exhibited slightly changes in the expression of synaptic proteins SNAP25 and vGLUT1, deregulation in mRNA levels of Fas and XIAP, and alteration in primary dendrites of granule cells in hippocampus. Interestingly, FAIM-KO mice were hyperactive, had impairment in cognitive tasks and in nest construction and exhibited an increase in social interactions. These results point to new exciting roles of FAIM1 in CNS. However, the use in this work of FAIM-KO mice derived of mixed background makes the replication of these experiments in other genetic background necessary for ensuring a role of FAIM1 in seizure susceptibility.