The cognitive defects of neonatally irradiated mice are accompanied by changed synaptic plasticity, adult neurogenesis and neuroinflammationReportar como inadecuado




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Molecular Neurodegeneration

, 9:57

First Online: 16 December 2014Received: 30 September 2014Accepted: 12 December 2014

Abstract

Background-purpose of the studyEpidemiological evidence suggests that low doses of ionising radiation ≤1.0 Gy produce persistent alterations in cognition if the exposure occurs at a young age. The mechanisms underlying such alterations are unknown. We investigated the long-term effects of low doses of total body gamma radiation on neonatally exposed NMRI mice on the molecular and cellular level to elucidate neurodegeneration.

ResultsSignificant alterations in spontaneous behaviour were observed at 2 and 4 months following a single 0.5 or 1.0 Gy exposure. Alterations in the brain proteome, transcriptome, and several miRNAs were analysed 6–7 months post-irradiation in the hippocampus, dentate gyrus DG and cortex. Signalling pathways related to synaptic actin remodelling such as the Rac1-Cofilin pathway were altered in the cortex and hippocampus. Further, synaptic proteins MAP-2 and PSD-95 were increased in the DG and hippocampus 1.0 Gy. The expression of synaptic plasticity genes Arc, c-Fos and CREB was persistently reduced at 1.0 Gy in the hippocampus and cortex. These changes were coupled to epigenetic modulation via increased levels of microRNAs miR-132-miR-212, miR-134. Astrogliosis, activation of insulin-growth factor-insulin signalling and increased level of microglial cytokine TNFα indicated radiation-induced neuroinflammation. In addition, adult neurogenesis within the DG was persistently negatively affected after irradiation, particularly at 1.0 Gy.

ConclusionThese data suggest that neurocognitive disorders may be induced in adults when exposed at a young age to low and moderate cranial doses of radiation. This raises concerns about radiation safety standards and regulatory practices.

KeywordsDendritic spines Hippocampus Cortex CREB miR-132 Ionising radiation Proteomics Rac1 Cofilin Alzheimer AbbreviationsANOVAAnalysis of variance

AMPAα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

CCortex

CNSCentral nervous system

CRCrest area

CTComputed tomography

DGDentate gyrus

DABDiaminobenzidine

FDRFalse discovery rate

GOGene ontology

HHippocampus

HLHilus

HPLCHigh pressure liquid chromatography

ICPLIsotope coded protein label

IBInfrapyramidal-blade

IEGImmediate-early response gene

IPAIngenuity pathway analysis

LC-MS-MSLiquid chromatography tandem mass spectrometry

LTPLong term potentiation

LTDLong term depression

MDAMalondialdehyde

miRNAmicroRNA

MLMolecular layer

NMDAN-methyl-D-aspartate

PND10Postnatal day 10

PBSPhosphate buffered saline

SBSuprapyramidal-blade

SDSSodium dodecyl sulphate

SEMStandard error of the mean

SGZSubgranular zone.

Electronic supplementary materialThe online version of this article doi:10.1186-1750-1326-9-57 contains supplementary material, which is available to authorized users.

Arianna Casciati, Sonja Buratovic contributed equally to this work.

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Autor: Stefan J Kempf - Arianna Casciati - Sonja Buratovic - Dirk Janik - Christine von Toerne - Marius Ueffing - Frauke Neff -

Fuente: https://link.springer.com/



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