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

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.