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

Abstract

Recent epidemiological data indicate that radiation doses as low as those used in computer tomography may result in long-term neurocognitive side effects. The aim of this study was to elucidate long-term molecular alterations related to memory formation in the brain after low and moderate doses of γ radiation. Female C57BL/6J mice were irradiated on postnatal day 10 with total body doses of 0.1, 0.5, or 2.0 Gy; the control group was sham-irradiated. The proteome analysis of hippocampus, cortex, and synaptosomes isolated from these brain regions indicated changes in ephrin-related, RhoGDI, and axonal guidance signaling. Immunoblotting and miRNA-quantification demonstrated an imbalance in the synapse morphology-related Rac1-Cofilin pathway and long-term potentiation-related cAMP response element-binding protein (CREB) signaling. Proteome profiling also showed impaired oxidative phosphorylation, especially in the synaptic mitochondria. This was accompanied by an early (4 weeks) reduction of mitochondrial respiration capacity in the hippocampus. Although the respiratory capacity was restored by 24 weeks, the number of deregulated mitochondrial complex proteins was increased at this time. All observed changes were significant at doses of 0.5 and 2.0 Gy but not at 0.1 Gy. This study strongly suggests that ionizing radiation at the neonatal state triggers persistent proteomic alterations associated with synaptic impairment.

Chronic low-dose-rate ionising radiation affects the hippocampal phosphoproteome in the ApoE−/− Alzheimer's mouse model

“…The reduction in lipid peroxidation seen here is similar to that observed in long-term after moderate doses of high-dose-rate radiation [20, 39]. These previous studies suggested a possible association with inactivated mitochondria producing less reactive oxygen species (ROS) [23, 39]. Low-dose radiation may activate the oxidative stress defense system and reduce ROS-related injuries such as lipid peroxidation [40].…”

“…CREB (cAMP response element-binding protein) is an essential transcription factor inhibited by ionising radiation [20, 23] and in AD [24]. Calcium signalling, one of the most significantly altered pathways related to synaptic plasticity in our study (Figure 2F), includes CREB signalling (Supplementary Table S5).…”

Ultrastructural Insights into the Biological Significance of Persisting DNA Damage Foci after Low Doses of Ionizing Radiation

“…Here, we show that the deleterious effects of low-dose irradiation are not limited to mitotically active precursor cells but may also affect nondividing neurons. Accumulation of radiation-induced DNA damage may induce ultrastructural changes in mature neurons, potentially affecting growth and branching of dendrites and spines (39,40). Altered synaptic plasticity may lead to functional changes in neuronal network activity and, consequently, to cognitive dysfunction with impairments in learning and memory performance and to changes in social behavior.…”

Progress in low dose health risk research

“…The strong overlap between gene expression profiles and phenotypes of prenatally irradiated mice and some neurological disorders (such as the microcephalic Magoh Mos2/+ mice[240]) suggests that the observed changes in gene expression are likely to affect normal brain functions after irradiation of embryonic mice. The radiation-induced changes in the p53 network of the embryonic brain thus appear to be of utmost importance for the developing brain[238].These alterations are in line with the persistent proteomic changes in synaptic plasticity related signalling in the mouse hippocampus and cortex observed in utero irradiated mice that appear to involve also deregulation of mitochondrial protein functions[233,234].N-methyl D-aspartate (NMDA) receptors are involved in the maturation and synapse establishment of neurons. X-ray doses ranging from 0.2 to 0.6 Gy were shown to induce neural cell death (apoptosis) which could be prevented by treatments with a non-competitive NMDA antagonist[241].Neural stem cells (NSCs) were found relatively resistant to oncogenesis from medium dose exposure (0.5 Gy) as compared to high dose exposure (3 Gy).…”

“…Indeed, there is a general concern about the possible long-term effects of low dose exposures to the brain [230]. More recently, it has been shown that cognitive effects of neonatal irradiated mice are accompanied by changed plasticity, adult neurogenesis and neuroinflammation [231,232] and that low dose IR affects mitochondria and synaptic signalling pathways in the murine hippocampus and cortex [233][234][235]. Also, high doses (1 Gy) of Xirradiation revealed short and long-term effects in terms of gene expression profiling and immune-histochemical alterations after IR exposure during early mouse brain development [236].…”