Modulation of hippocampal neuronal apoptosis and neurogenesis by Fas apoptotic inhibitory molecule 2 (Faim2) in the course of experimental streptococcal meningitis

Fas apoptotic inhibitory molecule 2 (Faim2) is a neuron-specific membrane protein and a member of the evolutionary conserved lifeguard (LFG) apoptosis regulatory gene family, acting as a proximal inhibitor of the Fas-FasL signaling pathway. Applying a Faim2-deficient null mutant mouse line, its involvement in neurological diseases with neuroprotective anti-apoptotic effects has recently been demonstrated in an in vivo model of focal cerebral ischemia. In this study, immediate and sustaining effects of Faim2 were investigated in a well-established mouse model of Streptococcus pneumoniae type 3 (SP3) meningitis. Leaving neuroinflammation, clinical course and survival unaltered, lack of Faim2 resulted in an increase of caspase-associated apoptotic cell death of hippocampal neurons during acute bacterial meningitis induced by subarachnoid infection with SP3 in mice. In Faim2 wild-type mice, neuroinflammation induced a divergent regulation of hippocampal Fas and Faim2 expression, revealing an increase of Fas and a decrease of Faim2 during acute bacterial meningitis. However, when mice were rescued by antibiotic treatment with ceftriaxone, Faim2-deficiency led to increased hippocampal neurogenesis several weeks after infection. As a sign for functional significance, this was associated with improved performance of Faim2-deficient mice compared to wild-type littermates in the Morris water maze, a paradigm for hippocampal spatial learning and memory, and increased exploratory behaviour. Additionally, clinical impairment and mortality was reduced and motor coordination improved related to Faim2-deficiency in ceftriaxone-treated cohorts. In summary, Faim2 influenced both neuroprotective and regenerative processes in a time-dependent manner in a mouse model of pneumococcal meningitis. Hence, modulation of Faim2 may offer new therapeutic approaches for improving outcome after bacterial meningitis.2014-01-1