Pneumococcal Cell Wall-Induced Meningitis Impairs Adult Hippocampal Neurogenesis

Abstract

Bacterial meningitis is a major infectious cause of neuronal degeneration in the hippocampus. Neurogenesis, a continuous process in the adult hippocampus, could ameliorate such loss. Yet the high rate of sequelae from meningitis suggests that this repair mechanism is inefficient. Here we used a mouse model of nonreplicative bacterial meningitis to determine the impact of transient intracranial inflammation on adult neurogenesis. Experimental meningitis resulted in a net loss of neurons, diminished volume, and impaired neurogenesis in the dentate gyrus for weeks following recovery from the insult. Inducible nitric oxide synthase (iNOS) immunoreactivity was prominent in microglia in nonproliferating areas of the dentate gyrus and hilus region after meningitis induction. Treatment with the specific iNOS inhibitor N6-(1-iminoethyl)-L-lysine restored neurogenesis in experimental meningitis. These data suggest that local central nervous system inflammation in and of itself suppresses adult neurogenesis by affecting both proliferation and neuronal differentiation. Repair of cognitive dysfunction following meningitis could be improved by intervention to interrupt these actively suppressive effects.

Thrombopoietin Contributes to Neuronal Damage in Experimental Bacterial Meningitis

“…Thus, a physiological role of the Tpo/c-Mpl system was postulated by which excess neurons are removed from the maturing brain (12). In bacterial meningitis, net loss of neurons and atrophy of the hippocampus may in part result from negative effects on neurogenesis (16), which could also involve Tpo signaling. In our mouse model of bacterial meningitis, however, most apoptotic cells in the dentate gyrus are mature, NeuN-positive neurons rather than immature cells (16).…”

“…In bacterial meningitis, net loss of neurons and atrophy of the hippocampus may in part result from negative effects on neurogenesis (16), which could also involve Tpo signaling. In our mouse model of bacterial meningitis, however, most apoptotic cells in the dentate gyrus are mature, NeuN-positive neurons rather than immature cells (16). In the present study, proapoptotic effects of rTpo were discernible only in infected mice, while no induction of apoptosis was observed in PBS-challenged control mice.…”

“…All animal experiments fully complied with federal and institutional guidelines and were approved by state authorities. Experiments were conducted in 8-to 12-week-old C57BL/6 wild-type mice and transgenic mice with homozygous c-Mpl ablation (c-Mpl Ϫ/Ϫ ) (1), using a wellestablished model of experimental meningitis (15)(16)(17)(18). During anesthesia with intraperitoneal ketamine (100 mg/kg of body weight; DeltaSelect) and xylazine (20 mg/kg; Bayer), a skin incision was made to expose the lumbar spine.…”

“…There is a high frequency of neurological sequelae in surviving patients. Neuropsychological deficits have been linked to neuronal loss and resulting atrophy of hippocampal structures (13,16,28). Both bacterial toxins and host-derived mediators contribute to neuronal damage (36).…”

Inhibition of Hippocampal Regeneration by Adjuvant Dexamethasone in Experimental Infant Rat Pneumococcal Meningitis

“…The modulation of the neuro-inflammation, particularly that caused by microglia, and its consequence on neurogenesis is complex (27). While studies of inflammatory meningitis by injection of pneumococcal cell wall (28) or lipopolysaccharides (29) were shown to have a negative impact on neurogenesis, we (20) and others (21) have demonstrated the opposite using models of productive bacterial infections. Consequently, inhibition of inflammation in these different experimental paradigms leads to different results.…”