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

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

Neonatal Irradiation Leads to Persistent Proteome Alterations Involved in Synaptic Plasticity in the Mouse Hippocampus and Cortex

“…61 In general, the molecular alterations in the Rac1-Cofilin pathway and the level of PSD-95 correlate well with our previous data showing persistent downregulation of Rac1 but increased expression of miR-132, miR-134 and total cofilin in irradiated NMRI mice. 17 The decreased expression of Rac1 is also one of the early (24 h) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 25 hallmarks of ionising radiation response both in mouse hippocampal neuronal HT22 cells and in hippocampus of NMRI mice. 26…”

“…15 At this specific stage, exposure to ionising radiation alone leads to long-term neurocognitive deficits characterised by pro-inflammatory changes, reflected in an increased number of activated microglia. 16,17 Pro-inflammatory factors produced by the activated microglia include IL-6, TNF-α, reactive oxygen species, and nitric oxide, all of which have been shown to suppress mitochondrial function. 18 Accruing data support a causal association between this early radiation exposure and long-term mitochondrial impairment in the brain.…”

“…Cognition was significantly impaired already at a dose of 0.5 Gy. 17 In the present study, we used female C57BL/6J mice to investigate the strain and gender specificity of the radiation effects. We also included exposure to a much lower dose, comparable to a cumulative dose after a few CT scans (0.1 Gy).…”

“…Three biological replicates were used within each group.Gene expression changes were considered to be significant if they reached a pvalue of ≤ 0.05 and if they had a fold-change of ≥ 1.2 or ≤ -1.2. The threshold of ±1.2 was based on the average experimental technical variance (8.4%) and biological variance (6.9%) of a set of 14 overlapping target genes as shown elsewhere 17. …”

Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome

“…To date, a number of studies have shown that both miRNAs are associated with impaired cognition when their expression levels are not maintained within a tightly regulated range (Scott et al 2012;Wang et al 2013;Kempf et al 2014). Moreover, while moderate overexpression (approximately fivefold increase) of miR-132 impairs learning and memory, small increases ( 1.5-fold) serve to facilitate performance on memoryassociated behavior tasks (Hansen et al 2013).…”