Altered GSK3β signaling in an infection-based mouse model of developmental neuropsychiatric disease

Willi, Roman; Harmeier, Anja; Giovanoli, Sandra; Meyer, Urs

doi:10.1016/j.neuropharm.2013.05.012

Cited by 33 publications

(20 citation statements)

References 48 publications

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“…Instead, these models highlight that synaptic elimination and envelopment of degenerating terminals can be a neuron autonomous event. Furthermore, our interpretation is also in line with other studies using the prenatal poly(I:C) administration model showing that significant neuronal and behavioral abnormalities can occur in the absence of overt microglia abnormalities (Garay et al, 2013;Missault et al, 2914;Pineda et al, 2013;Willi et al, 2013). Additional investigations will therefore be 25 needed to identify the cellular and molecular processes underlying the emergence of hippocampal synaptic deficits following prenatal immune challenge.…”

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confidence: 87%

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Giovanoli

Weber‐Stadlbauer

Schedlowski

et al. 2016

Brain, Behavior, and Immunity

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122

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Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre-and postsynaptic deficits. Using a well-established mouse model of maternal exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)-exposed and control mothers. We found that prenatal immune activation induced an adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early-life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial anomalies or systemic inflammation, adult offspring exposed to prenatal immune activation displayed increased hippocampal IL-1 levels. Taken together, our findings demonstrate that age-dependent synaptic deficits and abnormal pro-inflammatory cytokine expression can occur during postnatal brain maturation in the absence of microglial anomalies or systemic inflammation. AbstractPrenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre--and postsynaptic deficits.Using a well--established mouse model of maternal exposure to the viral mimetic polyriboinosinic--polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)--exposed and control mothers. We found that prenatal immune activation induced adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early--life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial a...

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supporting

confidence: 87%

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Giovanoli

Weber‐Stadlbauer

Schedlowski

et al. 2016

Brain, Behavior, and Immunity

Self Cite

122

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“…Some studies using rodent models of bacterial or viral maternal immune challenge have reported a significant upregulation of circulating inflammatory factors such as proinflammatory cytokines or chemokines in the juvenile or adult offspring (17,43,69). Other studies using the same animal models, however, failed to find clear signs of systemic inflammation in juvenile or adult offspring born to immunologically challenged mothers (96,157), or they even reported opposite effects that were characterized by blunted systemic inflammatory activity following prenatal infection (115).…”

Section: Peripheral (And Central) Inflammationmentioning

confidence: 99%

“…Enhanced microglia activation in brain parenchyma, along with increased central production of secreted inflammatory factors, is often taken as a sign of ongoing inflammation in the CNS (48). The possibility that prenatal infection leads to chronic signs of brain inflammation has been supported only by some studies in rats and mice (17,69), whereas other rodent studies failed to find evidence for such neuroinflammatory processes extending into neonatal or adult life (5,43,96,119,151,157).…”

Section: Peripheral (And Central) Inflammationmentioning

confidence: 99%

“…Indeed, it appears that more marked postnatal inflammatory changes are seen following relatively severe forms of maternal immune challenge, such as chronic exposure to immune system-activating agents throughout the entire gestational period (17). In contrast, acute or subchronic prenatal exposure to immune system-activating stimuli in mice and rats appears to be largely devoid of systemic and central inflammatory effects persisting into the juvenile or adult period (5,43,96,119,151,157). The latter may not seem surprising because inflammation is typically counteracted by homeostatic processes that mount antiinflammatory and/or immunosuppressive responses upon the induction of inflammation (132), which, in turn, dampen and finally resolve the post-acute fetal inflammatory responses to maternal immune activation (91).…”

Section: Peripheral (And Central) Inflammationmentioning

confidence: 99%

“…As reviewed in detail elsewhere (14,50), numerous experimental studies in rodents show that immunological exposure in early (prenatal or neonatal) life can cause the organism to mount differential (and often more vigorous) CNS inflammatory responses to subsequent immunological or nonimmunological challenges. For example, even though prenatal virus-like immune activation per se does not cause overt glial abnormalities and associated inflammatory changes in the brain parenchyma of mouse offspring (5,43,157), signs of microglia overactivation and exacerbated inflammatory cytokine secretion in CNS areas can be induced in these offspring when they are additionally exposed to subchronic stress postnatally (44). This form of immune sensitization or priming suggests that prenatal immune activation can markedly increase the vulnerability of the offspring to brain immune changes in response to stress.…”

Section: Peripheral (And Central) Inflammationmentioning

confidence: 99%

See 2 more Smart Citations

Long-term pathological consequences of prenatal infection: beyond brain disorders

Labouesse

Langhans

Meyer

2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Amphetamine Neurotoxicity in PC12 Cells through the PP2A/AKT/GSK3β Pathway

Yan

Pan

2018

Neurotox Res

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Amphetamine (AMPH) abuse can influence neuropsychiatric disorders and cell apoptosis by interfering with the protein kinase B/ glycogen synthase kinase 3 beta (AKT/GSK3β) pathway. However, the mechanisms underlying this regulation are poorly understood. Using PC12 cells, we found that AMPH inhibited AKT and GSK-3β phosphorylation levels and increased total GSK-3β levels. Furthermore, AMPH caused an increase in the activity of protein phosphatase 2 (PP2A), a signaling protein upstream of AKT, which in turn inhibited phosphorylated AKT levels. Okadaic acid, a PP2A inhibitor, protected PC12 cells against AMPH-induced apoptosis. Together, our results suggest that the PP2A/AKT/GSK3β pathway plays an important role in AMPH-induced neurotoxicity.

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Altered GSK3β signaling in an infection-based mouse model of developmental neuropsychiatric disease

Cited by 33 publications

References 48 publications

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Long-term pathological consequences of prenatal infection: beyond brain disorders

Amphetamine Neurotoxicity in PC12 Cells through the PP2A/AKT/GSK3β Pathway

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