A Single Low Dose of Proton Radiation Induces Long-Term Behavioral and Electrophysiological Changes in Mice

Abstract

Astronauts traveling outside Earth's magnetosphere risk exposure to charged particle radiation that may cause neurophysiological changes and behavioral deficits. Although proton particles comprise a large portion of the space radiation environment, little has been published on the effects of low-dose proton radiation on central nervous system function. In the current study, we irradiated young male mice with 0.5 Gy 150 MeV protons and assessed the effects on behavior and hippocampal neurophysiology. Spatial learning ability, a sensitive behavioral marker of hippocampal damage, was assessed using the water maze and Barnes maze before irradiation and repeatedly 3 and 6 months after irradiation. Evoked field excitatory postsynaptic potentials (fEPSPs) and population spikes, long-term potentiation (LTP) and spontaneous oscillations (SOs) triggered by incubation with Mg(2+)-free media (reflecting interictal epileptiform activity) were assessed 9 months after irradiation in vitro in hippocampal slice preparations. Irradiated mice exhibited impaired reversal learning in the water maze compared to control mice 6 months after irradiation. Proton radiation did not affect LTP, but significantly increased fEPSP slopes and reduced the incidence of SOs 9 months after irradiation. These findings suggest that a single exposure to low-dose proton radiation can increase synaptic excitability and suppress the propensity for epileptiform activity. Such findings of functional alterations in the irradiated mouse hippocampus have implications for extended manned space missions planned in the near future.

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“…The specificity of these effects indicate that proton irradiation does not indiscriminately affect the synaptic properties of neuronal circuits, in spite of the fact that the effect size was large, specifically, a more than sixfold increase in GABA release from CB 1 BCs without any alteration in the release properties from PVINs. The specificity and magnitude of these persistent alterations in perisomatic inhibitory circuits are consistent with the marked alterations in cognitive performance after space-relevant doses of radiation (Lonart et al 2012; Bellone et al 2015). Indeed, given the reported roles of CB 1 BCs in a variety of circuit functions, including the integration of synaptic inputs from a variety of local and long-distance sources, as well as in the modulation of the input–output gains of CA1 PCs during network activity and the expression of input-timing depending plasticity, the robust increase in GABA release from CB 1 BCs after proton irradiation likely affects the assessment of the saliency of inputs arriving at the hippocampus from the entorhinal cortex (Armstrong and Soltesz 2012; Basu et al 2013).…”

“…In the present study, we systemically examined the effects of space-relevant, low-dose proton irradiation on local synaptic circuits within the hippocampus, a brain area centrally important for some of the cognitive tasks affected by radiation exposure (Britten et al 2012, 2014; Bellone et al 2015). The key findings are: (1) Proton irradiation resulted in a large, persistent potentiation of action potential-dependent GABA release from CB 1 BCs onto CA1 PCs, without alterations in the axonal or dendritic morphology or intrinsic excitability of these interneurons; (2) The mechanism of the radiation-induced increase in GABA release from CB 1 BCs was a significant decrease in the CB 1 -mediated control of GABA release, associated with depressed 2-AG levels; (3) The effects of irradiation on GABA release were cell type-specific, since proton exposure did not alter GABA release from PVINs; (4) Local excitatory circuits were also modulated by radiation, as indicated by a proton-induced enhancement of the connection probability between PCs and PVINs, without significant increases in the PC to CB 1 BC connections.…”

“…For example, increased inhibitory inputs can cause paradoxical rebound spiking and increases in synchronized discharges in hippocampal circuits (Cobb et al1995; Chen et al 2001). Space-relevant irradiation using low doses of protons or high-energy charged particles (e.g., 28 Si and 56 Fe) generally resulted in an overall increase in hippocampal excitability as assessed by field EPSPs in the CA1 and the dentate gyrus (Vlkolinský et al 2007; Marty et al 2014; Rudobeck et al 2014; Bellone et al 2015). Similarly, reports indicating increases in postsynaptic density protein (PSD-95) expression, persistent sodium currents, and excitatory synaptic transmission are also consistent with hippocampal hyperexcitability caused by space-relevant irradiation (Parihar et al 2014; Sokolova et al 2015).…”

“…In particular, GABAergic interneurons in the hippocampus are known to underlie the emergence of theta and gamma oscillations (Klausberger and Somogyi 2008; Isaacson and Scanziani 2011; Hu et al 2014). These rhythms play key roles in spatial memory, attention, and cognitive flexibility (Fuchs et al 2007; Basu et al 2013; Cho et al 2015; Hanslmayr et al 2016; Kim et al 2016), which are behavioral tasks known to be impaired after low-dose charged particle irradiation (Britten et al 2012; Lonart et al 2012; Parihar et al 2014; Bellone et al 2015). Because space relevant exposures elicit cognitive deficits involving impaired hippocampus-dependent spatial memory (Britten et al 2012; Bellone et al 2015; Parihar et al 2015a), irradiation might compromise hippocampal GABAergic interneurons and/or their connectivity with excitatory cells.…”

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“…1,2 Proton particle irradiation has also been linked to deleterious behavioral outcomes. 3,4 Despite evidence showing impaired functioning following exposure to particle radiation, relatively few studies have assessed the effects of other types of radiation on behavioral endpoints.…”