Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice

Meyer, Urs; Nyffeler, Myriel; Yee, Benjamin K.; Knuesel, Irène; Feldon, Joram

doi:10.1016/j.bbi.2007.09.012

Cited by 416 publications

(413 citation statements)

References 75 publications

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“…It would be highly relevant, therefore, to check in the adult brain if oligodendrocytes, which express Reelin in vitro (Siebert and Osterhout, 2011) Importantly, we were recently able to demonstrate that a viral-like prenatal immune challenge predisposes the offspring to develop an AD-like phenotype, which is induced if the challenge is repeated for a second time during adulthood (Krstic et al, 2012a). In these prenatally challenged mice, the loss of Reelin expressing cells (Meyer et al, 2008, Knuesel et al, 2009 coincided with an increase in APP production and cleavage, Tau hyperphosphorylation and missorting, as well as cognitive deficits (Krstic et al, 2012a). This is in agreement with the observations of cognitive decline in aged rats correlating with reduced Reelin expression in the entorhinal cortex (Stranahan et al, 2011a), recently confirmed by the findings of impaired spatial memory following experimental interference with Reelin signaling in the same area (Stranahan et al, 2011b).…”

Section: And Promotesmentioning

confidence: 99%

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

et al. 2013

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Alzheimer's disease (AD) is one of the largest unmet medical concerns of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles, the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiological characteristic of late-onset AD. AbstractAlzheimer`s disease (AD) is one of the largest unmet medical needs of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles (NFTs), the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiology characteristic of late-onset AD.3

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Section: And Promotesmentioning

confidence: 99%

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

et al. 2013

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“…Prenatal immune activation induces both structural and functional abnormalities in the hippocampus (e.g., Meyer et al, 2008b), an area implicated in learning and memory (e.g., Broersen, 2000;Moser et al, 1993). Further, viral infections have been reported to reduce synaptic density and bring about neuronal loss (Sharma et al, 2002) and pyramidal cell atrophy in the hippocampus (Fatemi et al, 2002).…”

Section: Learning and Memorymentioning

confidence: 99%

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

Rana

Aavani

Pittman

2012

Hormones and Behavior

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Humans are exposed to potentially harmful agents (bacteria, viruses, toxins) throughout our lifespan; the consequences of such exposure can alter central nervous system development. Exposure to immunogens during pregnancy increases the risk of developing neurological disorders such as schizophrenia and autism. Further, sex hormones, such as estrogen, have strong modulatory effects on immune function and have also been implicated in the development of neuropathologies (e.g., schizophrenia and depression). Similarly, animal studies have demonstrated that immunogen exposure in utero or during the neonatal period, at a time when the brain is undergoing maturation, can induce changes in learning and memory, as well as dopaminemediated behaviors in a sex-specific manner. Literature that covers the effects of immunogens on innate immune activation and ultimately the development of the adult brain and behavior is riddled with contradictory findings, and the addition of sex as a factor only adds to the complexity. This review provides evidence that innate immune activation during critical periods of development may have effects on the adult brain in a sex-specific manner. Issues regarding sex bias in research as well as variability in animal models of immune function are discussed.

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“…Studies in the maternal infection model, the DISC1 model, and prenatal exposure to methylazoxymethanol acetate (MAM), have shown that alterations of brain development during specific periods of pre or postnatal development produce discrete disruptions that lead to behavioral and neurochemical effects that include a decreased number of PVinterneurons (Hikida et al, 2007;Lodge and Grace, 2007;Meyer et al, 2007;Lodge et al, 2009). In the MAM model, where the mitotoxin is applied during interneuronal proliferation/migration stage, the number of PV-interneurons decreased in specific brain regions that correlated with alterations in oscillatory activity and decreased lateral inhibition in adulthood (Lodge et al, 2009).…”

Section: Neurodevelopmental Origins Of Schizophrenia: Activation Of Tmentioning

confidence: 99%

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

2009

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An imbalance in the redox-state of the brain may be part of the underlying pathophysiology in schizophrenia. Inflammatory mediators, such as IL-6, which can tip the redox balance into a prooxidant state, have been consistently found to be altered in schizophrenia patients. However, the relationship of altered redox-state to altered brain functions observed in the disease has been unclear. Recent data from a pharmacological model of schizophrenia suggest that redox and inflammatory imbalances may be directly linked to the pathophysiology of the disease by alterations in fast-spiking interneurons. Repetitive adult-exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH-oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex. This effect is not observed after a single exposure to ketamine, suggesting that the first exposure to the NMDA-R antagonist primes the brain such that deleterious effects on PVinterneurons appear upon repetitive exposures. The effects of activation of the IL-6/Nox2 pathway on the PV-interneuronal system are reversible in the adult brain, but permanent in the developing cortex. The slow development of PV-interneurons, while essential for shaping of neuronal circuits during postnatal brain development, increases their vulnerability to deleterious insults that can permanently affect their maturational process. Thus, in individuals with genetic predisposition, the persistent activation of the IL-6/Nox2 pathway may be an environmental factor that tips the redoxbalance leading to schizophrenia symptoms in late adolescence and early adulthood.

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Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice

Cited by 416 publications

References 75 publications

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

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