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Primary olfactory cortex in autism and epilepsy: increased glial cells in autism
AbstractAutism Spectrum Disorder is characterized by sensory anomalies including impaired olfactory identification. Between 5 and 46 percent of individuals with autism have a clinical diagnosis of epilepsy. Primary olfactory cortex (piriform cortex) is central to olfactory identification and is an epileptogenic structure. Cytoarchitectural changes in olfactory cortex may underlie olfactory differences seen in autism. Primary olfactory cortex was sampled from 17 post‐mortem autism cases with and without epilepsy, 11 epilepsy cases without autism and 11 typically developed cases. Stereological and neuropathological methods were used to quantify glial, pyramidal and non‐pyramidal cell densities in layers of the piriform as well as identify pathological differences in this area and its neighbouring region, the olfactory tubercle. We found increased layer II glial cell densities in autism with and without epilepsy, which were negatively correlated with age and positively correlated with levels of corpora amylacea in layer I. These changes were also associated with greater symptom severity and did not extend to the olfactory tubercle. Glial cell organization may follow an altered trajectory of development with age in autism. The findings are consistent with other studies implicating increased glial cells in the autism brain. Altered cytoarchitecture may contribute to sensory deficits observed in affected individuals. This study provides evidence that autism is linked to alterations in the cytoarchitectural structure that underlies primary sensory processes and is not restricted to heteromodal (“higher”) cognitive centers.
Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development
AbstractSome neuropsychiatric disease, including schizophrenia, may originate during prenatal development, following periods of gestational hypoxia and placental oxidative stress. Here we investigated if gestational hypoxia promotes damaging secretions from the placenta that affect fetal development and whether a mitochondria-targeted antioxidant MitoQ might prevent this. Gestational hypoxia caused low birth-weight and changes in young adult offspring brain, mimicking those in human neuropsychiatric disease. Exposure of cultured neurons to fetal plasma or to secretions from the placenta or from model trophoblast barriers that had been exposed to altered oxygenation caused similar morphological changes. The secretions and plasma contained altered microRNAs whose targets were linked with changes in gene expression in the fetal brain and with human schizophrenia loci. Molecular and morphological changes in vivo and in vitro were prevented by a single dose of MitoQ bound to nanoparticles, which were shown to localise and prevent oxidative stress in the placenta but not in the fetus. We suggest the possibility of developing preventative treatments that target the placenta and not the fetus to reduce risk of psychiatric disease in later life.
Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology
The sustained proliferation of microglia is a key hallmark of Alzheimer’s disease (AD), accelerating its progression. Here, we sought to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesising that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We found that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterised by increased bgal activity, a senescence-associated transcriptional signature and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. Prevention of early microglial proliferation hindered the development of senescence and DAM, impairing the accumulation of Aβ, as well as associated neuritic and synaptic damage. Overall, our results support that excessive microglial proliferation leads to the generation of senescent DAM, which contribute to early Abpathology in AD.
Spatiotemporal dynamics of microglia across the human lifespan
Microglia, the brain’s resident macrophages, shape neural development and wiring, and are key neuroimmune hubs in the pathological signature of neurodevelopmental disorders. In the human brain, microglial development has not been carefully examined yet, and most of our knowledge derives from rodents. We established an extensive collection of 97 post-mortem tissues enabling quantitative, sex-matched, detailed analysis of microglia across the human lifespan. We identify the dynamics of these cells in the human telencephalon, describing novel waves in microglial density across gestation and infancy, controlled by a balance of proliferation and apoptosis, which track key neurodevelopmental milestones. These profound changes in microglia are also observed in bulk RNAseq and single-cell RNAseq datasets. This study provides insight and detail into the spatiotemporal dynamics of microglia across the human lifespan. Our findings serve as a solid foundation for elucidating how microglia contribute to shaping neurodevelopment in humans.
The Effects of Xenon Gas Inhalation on Neuropathology in a Placental-Induced Brain Injury Model in Neonates: A Pilot Study.
Improved obstetric and neonatal care have reduced the prevalence of severe hypoxic-ischemic-encephalopathy (HIE), however 1-3/1000 newborns in the developed world(1) suffer death or neurodevelopmental disability from HIE. The normal development of the brain during gestation can also be altered by placental reprogramming under oxidative stress. Under these conditions, the placenta releases DNA damaging molecules, bone morphogenic proteins, microRNAs, and glutamate(2). At present, one is unable to diagnose or treat these factors.