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Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway.

McDonald CR, Cahill LS, Ho KT, Yang J, Kim H, Silver KL, Ward PA, Mount HT, Liles WC, Sled JG, Kain KC - PLoS Pathog. (2015)

Bottom Line: The in utero environment profoundly impacts childhood neurodevelopment and behaviour.These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches.Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies in Africa are at risk of malaria in pregnancy (MIP) however the impact of in utero exposure to MIP on fetal neurodevelopment is unknown. Complement activation, in particular C5a, may contribute to neuropathology and adverse outcomes during MIP. We used an experimental model of MIP and standardized neurocognitive testing, MRI, micro-CT and HPLC analysis of neurotransmitter levels, to test the hypothesis that in utero exposure to malaria alters neurodevelopment through a C5a-C5aR dependent pathway. We show that malaria-exposed offspring have persistent neurocognitive deficits in memory and affective-like behaviour compared to unexposed controls. These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches. Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.

No MeSH data available.


Related in: MedlinePlus

In utero exposure to EMIP is associated with localized changes in tissue levels of major biogenic amines in offspring at 8 weeks of age.Tissue levels of (a) dopamine, and (b) serotonin in the frontal cortex, (c) norepinephrine in the temporoparietal cortex, (d) serotonin in the striatum, (e) serotonin and (f) norepinephrine in the cerebellum of unexposed (UE, n = 15) and malaria exposed (EX, n = 15) offspring. * P < 0.05, **P < 0.01, ***P < 0.005; T-Test. Box plots depict median, 95% confidence interval (box) and range (whiskers).
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ppat.1005140.g004: In utero exposure to EMIP is associated with localized changes in tissue levels of major biogenic amines in offspring at 8 weeks of age.Tissue levels of (a) dopamine, and (b) serotonin in the frontal cortex, (c) norepinephrine in the temporoparietal cortex, (d) serotonin in the striatum, (e) serotonin and (f) norepinephrine in the cerebellum of unexposed (UE, n = 15) and malaria exposed (EX, n = 15) offspring. * P < 0.05, **P < 0.01, ***P < 0.005; T-Test. Box plots depict median, 95% confidence interval (box) and range (whiskers).

Mentions: Examination by MRI or micro-CT may not be sufficiently sensitive to detect subtle neurological features, such as changes in neuronal connectivity, capable of altering neurocognitive outcomes. Therefore, we next investigated levels of biogenic amine transmitters (dopamine, norepinephrine and serotonin) in four regions of interest (frontal cortex, temporoparietal cortex, striatum and hippocampus) based on their previously established involvement in the behavioral phenotypes we observed [36–38]. All tissue was harvested from animals that had been tested behaviorally to confirm their phenotype (Fig 1C–1E). Wild-type malaria-exposed offspring showed decreased tissue levels of dopamine (P < 0.01; Fig 4A) and serotonin (P < 0.005; Fig 4B) in the frontal cortex, norephinephrine in the temporoparietal cortex (P < 0.05; Fig 4C) and serotonin in the striatum (P < 0.05; Fig 4D) compared with wild-type unexposed offspring. Tissue levels of the catecholamine metabolite homovanillic acid were reduced in the frontal cortex and hippocampus of wild-type exposed mice (P < 0.05; S4 Table). Tissue levels of these analytes in each of the regions tested are reported in S4 Table. Maternal peripheral parasitemia (ranging from 14–31% on the day of delivery; Fig 1A) was not associated with differences in the observed levels of major biogenic amines, MRI or micro-CT imaging or neurocognitive outcomes.


Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway.

McDonald CR, Cahill LS, Ho KT, Yang J, Kim H, Silver KL, Ward PA, Mount HT, Liles WC, Sled JG, Kain KC - PLoS Pathog. (2015)

In utero exposure to EMIP is associated with localized changes in tissue levels of major biogenic amines in offspring at 8 weeks of age.Tissue levels of (a) dopamine, and (b) serotonin in the frontal cortex, (c) norepinephrine in the temporoparietal cortex, (d) serotonin in the striatum, (e) serotonin and (f) norepinephrine in the cerebellum of unexposed (UE, n = 15) and malaria exposed (EX, n = 15) offspring. * P < 0.05, **P < 0.01, ***P < 0.005; T-Test. Box plots depict median, 95% confidence interval (box) and range (whiskers).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581732&req=5

ppat.1005140.g004: In utero exposure to EMIP is associated with localized changes in tissue levels of major biogenic amines in offspring at 8 weeks of age.Tissue levels of (a) dopamine, and (b) serotonin in the frontal cortex, (c) norepinephrine in the temporoparietal cortex, (d) serotonin in the striatum, (e) serotonin and (f) norepinephrine in the cerebellum of unexposed (UE, n = 15) and malaria exposed (EX, n = 15) offspring. * P < 0.05, **P < 0.01, ***P < 0.005; T-Test. Box plots depict median, 95% confidence interval (box) and range (whiskers).
Mentions: Examination by MRI or micro-CT may not be sufficiently sensitive to detect subtle neurological features, such as changes in neuronal connectivity, capable of altering neurocognitive outcomes. Therefore, we next investigated levels of biogenic amine transmitters (dopamine, norepinephrine and serotonin) in four regions of interest (frontal cortex, temporoparietal cortex, striatum and hippocampus) based on their previously established involvement in the behavioral phenotypes we observed [36–38]. All tissue was harvested from animals that had been tested behaviorally to confirm their phenotype (Fig 1C–1E). Wild-type malaria-exposed offspring showed decreased tissue levels of dopamine (P < 0.01; Fig 4A) and serotonin (P < 0.005; Fig 4B) in the frontal cortex, norephinephrine in the temporoparietal cortex (P < 0.05; Fig 4C) and serotonin in the striatum (P < 0.05; Fig 4D) compared with wild-type unexposed offspring. Tissue levels of the catecholamine metabolite homovanillic acid were reduced in the frontal cortex and hippocampus of wild-type exposed mice (P < 0.05; S4 Table). Tissue levels of these analytes in each of the regions tested are reported in S4 Table. Maternal peripheral parasitemia (ranging from 14–31% on the day of delivery; Fig 1A) was not associated with differences in the observed levels of major biogenic amines, MRI or micro-CT imaging or neurocognitive outcomes.

Bottom Line: The in utero environment profoundly impacts childhood neurodevelopment and behaviour.These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches.Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies in Africa are at risk of malaria in pregnancy (MIP) however the impact of in utero exposure to MIP on fetal neurodevelopment is unknown. Complement activation, in particular C5a, may contribute to neuropathology and adverse outcomes during MIP. We used an experimental model of MIP and standardized neurocognitive testing, MRI, micro-CT and HPLC analysis of neurotransmitter levels, to test the hypothesis that in utero exposure to malaria alters neurodevelopment through a C5a-C5aR dependent pathway. We show that malaria-exposed offspring have persistent neurocognitive deficits in memory and affective-like behaviour compared to unexposed controls. These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches. Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.

No MeSH data available.


Related in: MedlinePlus