HIPPOCAMPAL DENTATE GYRUS INJURY IN NEONATAL BACTERIAL

University Of California San Francisco, San Francisco CA

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Abstract

Bacterial meningitis in newborns leads to brain damage and subsequent neurologic sequelae including learning and memory deficits. In an infant rat model of neonatal bacterial meningitis, damage to the dentate gyrus of the hippocampal formation occurred regularly and showed two fundamentally distinct forms: (1) Scattered apoptotic injury confined to cells in the subgranular zone and (2) injury of the lower blade of the dentate gyrus with clusters of pyknotic appearing cells. Since the hippocampus is critical for learning and memory function, damage to it may be the basis for the learning deficits in survivors of bacterial meningitis. Indeed, damage to the dentate gyrus was associated with learning deficits in experimental meningitis. The dentate gyrus of the hippocampus is unique in two respects. First, the morphogenesis occurs very late in development in both rodents and humans, perhaps making it more vulnerable to pathologic insult at later developmental stages than other brain regions. Second, the dentate gyrus is a continuously developing system throughout life, containing progenitor cells able to multiply and give rise to new neurons. This has been implicated in the ability to form new memories and learn new tasks later in life. In meningitis, the progenitor cells appear to be selectively damaged. We will test the hypothesis that bacterial meningitis in young animals leads to selective damage within the dentate gyrus, including the progenitors or their immediate progeny, giving rise to neuroanatomical and functional abnormalities that underlie some of the permanent neurologic deficits affecting survivors of bacterial meningitis. Specifically, we will determine the nature of cell death in the dentate gyrus (apoptosis or necrosis); we will identify the cells damaged by the meningitic process )progenitor cells, immature or mature granule cell neurons, interneurons, glia); we will identify pathophysiologic factors leading to cell death (e.g., ischemia, excitatory amino acids, oxygen radicals, cytokines); and we will define in adult animals the neuroanatomical and functional consequences of damage to the immature dentate gyrus.