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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

Quantitative analysis of fetal cerebral vasculature using a vessel segmentation algorithm determined (a) the number of vessel segments and (b) the total length of all vessel segments (mm) of wild-type unexposed (WT UE, n = 8), wild-type malaria exposed (WT EX, n = 7), C5a receptor knockout unexposed (C5ar-/- UE, n = 7) and C5a receptor knockout malaria-exposed (C5ar-/- EX, n = 7) offspring.*P < 0.05; ANCOVA and post-test. Box plots depict median and interquartile range.
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ppat.1005140.g003: Quantitative analysis of fetal cerebral vasculature using a vessel segmentation algorithm determined (a) the number of vessel segments and (b) the total length of all vessel segments (mm) of wild-type unexposed (WT UE, n = 8), wild-type malaria exposed (WT EX, n = 7), C5a receptor knockout unexposed (C5ar-/- UE, n = 7) and C5a receptor knockout malaria-exposed (C5ar-/- EX, n = 7) offspring.*P < 0.05; ANCOVA and post-test. Box plots depict median and interquartile range.

Mentions: Previous studies have shown that malaria in pregnancy is associated with altered placental vascular development [5]. We hypothesized that fetal cerebral vasculature may also be modified in malaria-exposed offspring, and that altered cerebrovascular development may contribute to the observed neurocognitive phenotype. Using a novel imaging approach in fetal mice, we performed micro-CT scans of fetal cerebral vasculature at G18. To our knowledge, this is the first time micro-CT has been used to visualize fetal cerebral vasculature. Using this technique, we identified all major cerebral vessels in fetuses and determined that there were no qualitative differences in major vessel architecture (Fig 2A–2D, S3 Table). In order to assess the impact of malaria–exposure on small vessel development, we further examined fetal cerebral vasculature with automated vessel tracking of the 3D images [35]. Vessel tracking analysis revealed a significant increase in the total number of vessel segments associated with in utero malaria-exposure (Fig 3A, P < 0.05). Malaria-exposure did not result in significant changes to total vessel length (Fig 3B).


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)

Quantitative analysis of fetal cerebral vasculature using a vessel segmentation algorithm determined (a) the number of vessel segments and (b) the total length of all vessel segments (mm) of wild-type unexposed (WT UE, n = 8), wild-type malaria exposed (WT EX, n = 7), C5a receptor knockout unexposed (C5ar-/- UE, n = 7) and C5a receptor knockout malaria-exposed (C5ar-/- EX, n = 7) offspring.*P < 0.05; ANCOVA and post-test. Box plots depict median and interquartile range.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1005140.g003: Quantitative analysis of fetal cerebral vasculature using a vessel segmentation algorithm determined (a) the number of vessel segments and (b) the total length of all vessel segments (mm) of wild-type unexposed (WT UE, n = 8), wild-type malaria exposed (WT EX, n = 7), C5a receptor knockout unexposed (C5ar-/- UE, n = 7) and C5a receptor knockout malaria-exposed (C5ar-/- EX, n = 7) offspring.*P < 0.05; ANCOVA and post-test. Box plots depict median and interquartile range.
Mentions: Previous studies have shown that malaria in pregnancy is associated with altered placental vascular development [5]. We hypothesized that fetal cerebral vasculature may also be modified in malaria-exposed offspring, and that altered cerebrovascular development may contribute to the observed neurocognitive phenotype. Using a novel imaging approach in fetal mice, we performed micro-CT scans of fetal cerebral vasculature at G18. To our knowledge, this is the first time micro-CT has been used to visualize fetal cerebral vasculature. Using this technique, we identified all major cerebral vessels in fetuses and determined that there were no qualitative differences in major vessel architecture (Fig 2A–2D, S3 Table). In order to assess the impact of malaria–exposure on small vessel development, we further examined fetal cerebral vasculature with automated vessel tracking of the 3D images [35]. Vessel tracking analysis revealed a significant increase in the total number of vessel segments associated with in utero malaria-exposure (Fig 3A, P < 0.05). Malaria-exposure did not result in significant changes to total vessel length (Fig 3B).

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