Modulation hippokampaler neuronaler Apoptose und Neurogenese durch Fas apoptotic inhibitory molecule 2 (Faim2) im Rahmen der experimentellen Streptokokkenmeningitis

Modulation hippokampaler neuronaler Apoptose und Neurogenese durch Fas apoptotic inhibitory molecule 2 (Faim2) im Rahmen der experimentellen Streptokokkenmeningitis

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

Kristian Harms

Doctoral thesis

Date of Examination: 2014-01-07

Date of issue: 2014-01-06

Advisor: Schulz, Jörg B. Prof. Dr.

Referee: Schulz, Jörg B. Prof. Dr.

Referee: Spreer, Annette PD Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0022-60AA-7

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Abstract

English

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.

Keywords: Fas apoptotic inhibitory molecule 2 (Faim2); lifeguard (LFG); Fas/CD95; Streptococcus pneumoniae; bacterial meningitis; neuroinflammation; hippocampal apoptosis and neurogenesis; spatial learning and memory; Morris water maze; neuroprotection; neuroregeneration

Schlagwörter: Fas apoptotic inhibitory molecule 2 (Faim2); lifeguard (LFG); Fas/CD95; Streptococcus pneumoniae; bakterielle Meningitis; Neuroinflammation; hippokampale Apoptose und Neurogenese; räumliches Lernen und Gedächtnis; Morris-Wasserlabyrinth; Neuroprotektion; Neuroregeneration