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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

Reduced tissue levels of biogenic amine transmitters were observed in wild-type malaria exposed, but not in C5a receptor knockout offspring, relative to unexposed controls.Brain tissue level of (a) dopamine (DA) and (b) serotonin (5HT) in the frontal cortex, (c) norepinephrine (NE) in the temporoparietal cortex and (d) serotonin (5HT) in the striatum, (e) norepinephrine and (f) serotonin in the cerebellum of wild type malaria exposed offspring (WT EX, n = 15) expressed relative to malaria unexposed wild type offspring and C5a receptor knockout unexposed offspring expressed relative to malaria unexposed C5ar-/- offspring (C5ar-/-EX, n = 15). In utero exposure to EMIP induced dysregulated messenger ribonucleic acid (mRNA) transcription level of BDNF in the fetal brain at gestational day 19. Fetal brain mRNA transcript level expressed as normalized copy number of (g) BDNF. *P < 0.05, **P < 0.01, ***P < 0.005; T-test (a-f) and one-way ANOVA (g). Box plots depict median, 95% confidence interval (box) and range (whiskers).
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ppat.1005140.g006: Reduced tissue levels of biogenic amine transmitters were observed in wild-type malaria exposed, but not in C5a receptor knockout offspring, relative to unexposed controls.Brain tissue level of (a) dopamine (DA) and (b) serotonin (5HT) in the frontal cortex, (c) norepinephrine (NE) in the temporoparietal cortex and (d) serotonin (5HT) in the striatum, (e) norepinephrine and (f) serotonin in the cerebellum of wild type malaria exposed offspring (WT EX, n = 15) expressed relative to malaria unexposed wild type offspring and C5a receptor knockout unexposed offspring expressed relative to malaria unexposed C5ar-/- offspring (C5ar-/-EX, n = 15). In utero exposure to EMIP induced dysregulated messenger ribonucleic acid (mRNA) transcription level of BDNF in the fetal brain at gestational day 19. Fetal brain mRNA transcript level expressed as normalized copy number of (g) BDNF. *P < 0.05, **P < 0.01, ***P < 0.005; T-test (a-f) and one-way ANOVA (g). Box plots depict median, 95% confidence interval (box) and range (whiskers).

Mentions: We next extended our analysis to examine the impact of EMIP-exposure on monoamine transmitter levels in adult WT and C5ar-/- mice. In contrast to EMIP-exposed WT mice, regional brain levels of biogenic amines were not significantly decreased in EMIP-exposed C5ar-/- offspring (P>0.05, Students t-test, S5 Table). We normalized the levels of transmitters of EMIP-exposed WT and C5ar-/- offspring to the mean of their respective unexposed controls (Fig 6A–6F). Exposed C5ar-/- offspring displayed significantly higher levels of serotonin in the frontal cortex (P = 0.0028; Fig 6B), norepinephrine in the temporoparietal cortex (P = 0.012; Fig 6C) and serotonin in the striatum (P = 0.009; Fig 6D), compared to EMIP-exposed WT mice. Given the established role of BDNF in regulating brain monoamine levels [40,41], we determined whether decreased fetal brain BNDF levels were associated with the observed decrease in biogenic amines and whether disruption of C5aR signaling would rescue these levels. We observed decreased BDNF transcript levels in EMIP-exposed WT offspring (Fig 6G); whereas BDNF levels were restored in EMIP-exposed C5ar-/- offspring (one-way ANOVA and post-test, P <0.001, Fig 6G).


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)

Reduced tissue levels of biogenic amine transmitters were observed in wild-type malaria exposed, but not in C5a receptor knockout offspring, relative to unexposed controls.Brain tissue level of (a) dopamine (DA) and (b) serotonin (5HT) in the frontal cortex, (c) norepinephrine (NE) in the temporoparietal cortex and (d) serotonin (5HT) in the striatum, (e) norepinephrine and (f) serotonin in the cerebellum of wild type malaria exposed offspring (WT EX, n = 15) expressed relative to malaria unexposed wild type offspring and C5a receptor knockout unexposed offspring expressed relative to malaria unexposed C5ar-/- offspring (C5ar-/-EX, n = 15). In utero exposure to EMIP induced dysregulated messenger ribonucleic acid (mRNA) transcription level of BDNF in the fetal brain at gestational day 19. Fetal brain mRNA transcript level expressed as normalized copy number of (g) BDNF. *P < 0.05, **P < 0.01, ***P < 0.005; T-test (a-f) and one-way ANOVA (g). Box plots depict median, 95% confidence interval (box) and range (whiskers).
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Related In: Results  -  Collection

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ppat.1005140.g006: Reduced tissue levels of biogenic amine transmitters were observed in wild-type malaria exposed, but not in C5a receptor knockout offspring, relative to unexposed controls.Brain tissue level of (a) dopamine (DA) and (b) serotonin (5HT) in the frontal cortex, (c) norepinephrine (NE) in the temporoparietal cortex and (d) serotonin (5HT) in the striatum, (e) norepinephrine and (f) serotonin in the cerebellum of wild type malaria exposed offspring (WT EX, n = 15) expressed relative to malaria unexposed wild type offspring and C5a receptor knockout unexposed offspring expressed relative to malaria unexposed C5ar-/- offspring (C5ar-/-EX, n = 15). In utero exposure to EMIP induced dysregulated messenger ribonucleic acid (mRNA) transcription level of BDNF in the fetal brain at gestational day 19. Fetal brain mRNA transcript level expressed as normalized copy number of (g) BDNF. *P < 0.05, **P < 0.01, ***P < 0.005; T-test (a-f) and one-way ANOVA (g). Box plots depict median, 95% confidence interval (box) and range (whiskers).
Mentions: We next extended our analysis to examine the impact of EMIP-exposure on monoamine transmitter levels in adult WT and C5ar-/- mice. In contrast to EMIP-exposed WT mice, regional brain levels of biogenic amines were not significantly decreased in EMIP-exposed C5ar-/- offspring (P>0.05, Students t-test, S5 Table). We normalized the levels of transmitters of EMIP-exposed WT and C5ar-/- offspring to the mean of their respective unexposed controls (Fig 6A–6F). Exposed C5ar-/- offspring displayed significantly higher levels of serotonin in the frontal cortex (P = 0.0028; Fig 6B), norepinephrine in the temporoparietal cortex (P = 0.012; Fig 6C) and serotonin in the striatum (P = 0.009; Fig 6D), compared to EMIP-exposed WT mice. Given the established role of BDNF in regulating brain monoamine levels [40,41], we determined whether decreased fetal brain BNDF levels were associated with the observed decrease in biogenic amines and whether disruption of C5aR signaling would rescue these levels. We observed decreased BDNF transcript levels in EMIP-exposed WT offspring (Fig 6G); whereas BDNF levels were restored in EMIP-exposed C5ar-/- offspring (one-way ANOVA and post-test, P <0.001, Fig 6G).

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