Neuronal Cell Death and Astrogliosis in the Developing Human Brain and Changes Seen in Sudden Infant Death Syndrome (SIDS)

Abstract

Sudden infant death syndrome (SIDS) is the sudden and unexplained death of a seemingly healthy infant. The mechanism of death remains unknown, although several risk factors and neuropathological changes have been identified. The mechanism by which increased cell death occurs in the SIDS hippocampus is not known, although nicotinic acetylcholine receptors (nAChRs) are thought to have a role in regulating cell death. Whether the SIDS hippocampus also has a reduced number of neurons and/or astrogliosis, key features of hippocampal sclerosis (HS), is not known. Finally, it remains unclear whether astrogliosis occurs in other regions of the SIDS brain. Using immunohistochemistry, markers of cell death (active caspase-3 and TUNEL), nAChR subunits (α7 and β2), neurons (Neuronal Nuclei (NeuN)) and astrocytes (glial fibrillary acidic protein (GFAP)) were explored in the developing hippocampus, while GFAP was explored in a range of brain regions across 2 separate research cohorts for comparison (UK and Australia). Analysis was undertaken to determine whether there were changes associated with SIDS or its risk factors. Results showed that SIDS infants had increased cell death and altered nAChR expression throughout the hippocampus, with correlations between the two, and notable associations with the presence of an upper respiratory tract infection (URTI). HS could not be explored in the context of SIDS, given that NeuN immunostaining was suboptimal, and assessment of cell loss utilising basic histochemical stains proved unreliable. SIDS infants in the UK showed increased GFAP in several brain regions, with various changes according to risk factors. These changes were not reproducible in the Australian cohort, which demonstrated different outcomes. In conclusion, this thesis supports that hypoxia and inflammation, due to the presence of the risk factors, are activated, leading to altered brain pathology in SIDS, including increased cell death, altered nAChRs, and astrogliosis.