Prenatal protein malnutrition decreases KCNJ3 and 2DG activity in rat prefrontal cortex

Amaral, André Cestonaro do; Jakovcevski, Mira; McGaughy, Jill; Calderwood, Stuart K.; Mokler, David J.; Rushmore, R. Jarrett; Galler, Janina R.; Akbarian, Schahram; Rosene, Douglas L.

doi:10.1016/j.neuroscience.2014.11.005

Cited by 11 publications

(11 citation statements)

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“…These findings significantly extend previous work reporting epigenetic dysregulation after prenatal malnutrition(36, 40–42). Given that DNA and histone methylation landscapes show highly dynamic developmental regulation of neuronal and to some extent also non-neuronal chromatin of human cerebral cortex during infancy and early childhood(43–47), the blood DNA methylation changes as reported here could reflect on epigenetic maladaptations in brain, in analogy to epigenetic changes in the brain and behavioral dysregulation in response to early life adversity(48, 49).…”

Section: Discussionsupporting

confidence: 89%

“…All animals maintained approximately neutral side biases for lever pressings (MAL=0.41±0.01; CON=0.42±0.02). Of note, adult rats exposed to malnourishment during development show region-specific glucose hypometabolism in rostro-medial cerebral cortex(36), considered the homolog of frontal association cortex in primates (37). We tested whether these neural are affected by altered expression of differentially methylated genes associated with attention and cognition in our human cohort.…”

Section: Resultsmentioning

confidence: 99%

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DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition

Peter

Fischer

Kundaković

et al. 2016

Biological Psychiatry

125

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Background Early childhood malnutrition affects 113 million children worldwide, impacting health and increasing vulnerability for cognitive and behavioral disorders later in life. Molecular signatures after childhood malnutrition, including the potential for intergenerational transmission, remain unexplored. Methods We surveyed blood DNA methylomes (~483,000 individual CpG sites) in 168 subjects across two generations (G1,G2), including 50 G1 individuals hospitalized during the first year of life for moderate to severe protein energy malnutrition, then followed up to 48 years in the Barbados Nutrition Study. Attention deficits and cognitive performance were evaluated with Connors Adult Attention Rating Scale (CAARS) and Wechsler Abbreviated Scale of Intelligence (WASI). Expression of nutrition-sensitive genes was explored by qRT-PCR in rat prefrontal cortex. Results We identified altogether 134 nutrition-sensitive differentially methylated genomic regions (DMR), with the overwhelming majority (87%) specific for G1. Multiple neuropsychiatric risk genes, including COMT, IFNG, MIR200B, SYNGAP1 and VIP2R showed associations of specific methyl-CpGs with attention and IQ. Interferon Gamma (IFNG) expression was decreased in prefrontal cortex of rats showing attention deficits after developmental malnutrition. Conclusions Early childhood malnutrition entails long lasting epigenetic signatures associated with liability for attention and cognition, and limited potential for intergenerational transmission.

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition

Peter

Fischer

Kundaković

et al. 2016

Biological Psychiatry

125

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“…Sections were exposed at -80 °C for ten days. After that, films were developed, fixed, and then digitized for the uptake of 2-DG followed the methods described previously 56 .…”

Section: Methodsmentioning

confidence: 99%

Comprehensive Application of Time-of-flight Secondary Ion Mass Spectrometry (TOF-SIMS) for Ionic Imaging and Bio-energetic Analysis of Club Drug-induced Cognitive Deficiency

Youn

Chen

Chiou

et al. 2015

Sci Rep

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Excessive exposure to club drug (GHB) would cause cognitive dysfunction in which impaired hippocampal Ca2+-mediated neuroplasticity may correlate with this deficiency. However, the potential changes of in vivo Ca2+ together with molecular machinery engaged in GHB-induced cognitive dysfunction has never been reported. This study aims to determine these changes in bio-energetic level through ionic imaging, spectrometric, biochemical, morphological, as well as behavioral approaches. Adolescent rats subjected to GHB were processed for TOF-SIMS, immunohistochemistry, biochemical assay, together with Morris water maze to detect the ionic, molecular, neurochemical, and behavioral changes of GHB-induced cognitive dysfunction, respectively. Extent of oxidative stress and bio-energetics were assessed by levels of lipid peroxidation, Na+/K+ ATPase, cytochrome oxidase, and [14C]-2-deoxyglucose activity. Results indicated that in GHB intoxicated rats, decreased Ca2+ imaging and reduced NMDAR1, nNOS, and p-CREB reactivities were detected in hippocampus. Depressed Ca2+-mediated signaling corresponded well with intense oxidative stress, diminished Na+/K+ ATPase, reduced COX, and decreased 2-DG activity, which all contributes to the development of cognitive deficiency. As impaired Ca2+-mediated signaling and oxidative stress significantly contribute to GHB-induced cognitive dysfunction, delivering agent(s) that improves hippocampal bio-energetics may thus serve as a promising strategy to counteract the club drug-induced cognitive dysfunction emerging in our society nowadays.

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“…Sections were exposed at -80 o C for ten days. After that, films were developed, fixed, and then digitized for the uptake of 2-DG followed the methods described previously [35].…”

Section: Hippocampal Bio-energetic Mapping With [ 14 C]-2-deoxyglucose (2-dg)mentioning

confidence: 99%

Melatonin Effectively Preserves Cognitive Function in Club Drug Intoxicated Rats

Huang¹,

Wc²,

Chen³

et al. 2018

Journal of Cell Biology and Histology

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Background: Excessive exposure to club drug gamma-hydroxybutyric acid (GHB) would cause cognitive dysfunction in which impaired Ca 2+ -mediated neuroplasticity in hippocampus may play an essential role in the pathogenesis of this deficiency. Considering melatonin is positive for neuroplastic regulation, the present study aims to determine whether melatonin would exert a neuro-protective effect on cognitive function following GHB. Materials and Methods: Adolescent rats subjected to ten days of GHB (500 mg/kg) and received 10 or 100 mg/kg of melatonin were processed for time-of-flight secondary ion mass spectrometry (TOF-SIMS), quantitative immunohistochemistry, biochemical and radiographic assay, together with Morris water maze to analyze the ionic, neurochemical, bio-energetic, and behavioral effects of melatonin on GHB-induced cognitive dysfunction, respectively. Results: In GHB intoxicated rats, decreased Ca 2+ imaging and depressed Ca 2+ -mediated signaling were detected in hippocampal neurons. The diminished expression of these signaling molecules corresponded well with intense oxidative stress, reduced bio-energetics, and poor performances in cognitive activities. However, in rats received different doses of melatonin during GHB intoxication, all above parameters were gradually returned to nearly normal levels in which the maximal change was detected in animals given the dose of 100 mg/kg. Conclusion:As melatonin effectively preserves cognitive function by saving the hippocampal bio-energetics through maintaining the Ca 2+ -mediated neuroplasticity, therapeutic use of melatonin may thus serve as a promising strategy to improve or counteract cognitive dysfunction induced by drug addiction prevailing in our society nowadays.

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Prenatal protein malnutrition decreases KCNJ3 and 2DG activity in rat prefrontal cortex

Cited by 11 publications

References 48 publications

DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition

DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition

Comprehensive Application of Time-of-flight Secondary Ion Mass Spectrometry (TOF-SIMS) for Ionic Imaging and Bio-energetic Analysis of Club Drug-induced Cognitive Deficiency

Melatonin Effectively Preserves Cognitive Function in Club Drug Intoxicated Rats

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