Radiation-Induced Alterations in Synaptic Neurotransmission of Dentate Granule Cells Depend on the Dose and Species of Charged Particles

Marty, Vincent; Vlkolinský, Roman; Minassian, N.; Cohen, Tamira; Nelson, Gregory A.; Spigelman, Igor

doi:10.1667/rr13647.1

Cited by 49 publications

(26 citation statements)

References 53 publications

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“…1B and D). This finding corroborates our recent findings observed in hippocampal slices of C57BL/6J mice by multielectrode array, in which neurons of the dentate gyrus irradiated with 1 Gy protons exhibited enhanced synaptic excitability (33). We speculate that the enhancing effects may be related to increases of synaptic density, such as the PSD-95 complex, which was recently described in a proton-irradiated hippocampus (9), or due to reduced GABAergic inhibitory tone (33) that limits the magnitude of excitatory field potentials (39) in functionally intact tissue.…”

Section: Discussionsupporting

confidence: 93%

“…Inhibition of neurogenesis could be detected after whole-body irradiation with proton doses as low as 0.5 Gy (28). Although several functional decrements in Alzheimer's disease (29)(30)(31)(32) and in the irradiated brain (14,33) are clearly similar and are likely related, the effects of radiation on other, perhaps less obvious but significant, functional manifestations in Alzheimer's disease have never been tested. For example, the propensity for epileptiform activity (34) and altered oscillatory properties in the local hippocampal networks (35,36) have been described in Alzheimer's disease, but have never been tested in irradiated neuronal tissue.…”

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confidence: 99%

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

Bellone¹,

Rudobeck

Hartman³

et al. 2015

Radiation Research

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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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Section: Discussionsupporting

confidence: 93%

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confidence: 99%

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

Bellone¹,

Rudobeck

Hartman³

et al. 2015

Radiation Research

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“…In other published work with these 28 Si doses, no change in key electrophysiological parameters in the mouse DG was reported at 3 months postirradiation (101), although those data were generated with more energetic (and perhaps less damaging) 28 Si particles than ours. Might these behavioral changes be due instead to 28 Si radiation-induced changes in neurogenesis?…”

Section: Discussioncontrasting

confidence: 59%

Whole-Body Exposure to²⁸Si-Radiation Dose-Dependently Disrupts Dentate Gyrus Neurogenesis and Proliferation in the Short Term and New Neuron Survival and Contextual Fear Conditioning in the Long Term

et al. 2017

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Astronauts traveling to Mars will be exposed to chronic low doses of galactic cosmic space radiation, which contains highly charged, high-energy (HZE) particles. 56Fe-HZE-particle exposure decreases hippocampal dentate gyrus (DG) neurogenesis and disrupts hippocampal function in young adult rodents, raising the possibility of impaired astronaut cognition and risk of mission failure. However, far less is known about how exposure to other HZE particles, such as 28Si, influences hippocampal neurogenesis and function. To compare the influence of 28Si exposure on indices of neurogenesis and hippocampal function with previous studies on 56Fe exposure, 9-week-old C57BL/6J and Nestin-GFP mice (NGFP; made and maintained for 10 or more generations on a C57BL/6J background) received whole-body 28Si-particle-radiation exposure (0, 0.2 and 1 Gy, 300 MeV/n, LET 67 KeV/µ, dose rate 1 Gy/min). For neurogenesis assessment, the NGFP mice were injected with the mitotic marker BrdU at 22 h postirradiation and brains were examined for indices of hippocampal proliferation and neurogenesis, including Ki67+, BrdU+, BrdU+NeuN+ and DCX+ cell numbers at short- and long-term time points (24 h and 3 months postirradiation, respectively). In the short-term group, stereology revealed fewer Ki67+, BrdU+ and DCX+ cells in 1-Gy-irradiated group relative to nonirradiated control mice, fewer Ki67+ and DCX+ cells in 0.2 Gy group relative to control group and fewer BrdU+ and DCX+ cells in 1 Gy group relative to 0.2 Gy group. In contrast to the clearly observed radiation-induced, dose-dependent reductions in the short-term group across all markers, only a few neurogenesis indices were changed in the long-term irradiated groups. Notably, there were fewer surviving BrdU+ cells in the 1 Gy group relative to 0- and 0.2-Gy-irradiated mice in the long-term group. When the short- and long-term groups were analyzed by sex, exposure to radiation had a similar effect on neurogenesis indices in male and female mice, although only male mice showed fewer surviving BrdU+ cells in the long-term group. Fluorescent immunolabeling and confocal phenotypic analysis revealed that most surviving BrdU+ cells in the long-term group expressed the neuronal marker NeuN, definitively confirming that exposure to 1 Gy 28Si radiation decreased the number of surviving adult-generated neurons in male mice relative to both 0- and 0.2-Gy-irradiated mice. For hippocampal function assessment, 9-week-old male C57BL/6J mice received whole-body 28Si-particle exposure and were then assessed long-term for performance on contextual and cued fear conditioning. In the context test the animals that received 0.2 Gy froze less relative to control animals, suggesting decreased hippocampal-dependent function. However, in the cued fear conditioning test, animals that received 1 Gy froze more during the pretone portion of the test, relative to controls and 0.2-Gy-irradiated mice, suggesting enhanced anxiety. Compared to previously reported studies, these data suggest that 28Si-radiation exposure damag...

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“…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).…”

Section: Discussionmentioning

confidence: 99%

Neurophysiology of space travel: energetic solar particles cause cell type-specific plasticity of neurotransmission

et al. 2016

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In the not too distant future, humankind will embark on one of its greatest adventures, the travel to distant planets. However, deep space travel is associated with an inevitable exposure to radiation fields. Space-relevant doses of protons elicit persistent disruptions in cognition and neuronal structure. However, whether space-relevant irradiation alters neurotransmission is unknown. Within the hippocampus, a brain region crucial for cognition, perisomatic inhibitory control of pyramidal cells (PCs) is supplied by two distinct cell types, the cannabinoid type 1 receptor (CB1)-expressing basket cells (CB1BCs) and parvalbumin (PV)-expressing interneurons (PVINs). Mice subjected to low-dose proton irradiation were analyzed using electrophysiological, biochemical and imaging techniques months after exposure. In irradiated mice, GABA release from CB1BCs onto PCs was dramatically increased. This effect was abolished by CB1 blockade, indicating that irradiation decreased CB1-dependent tonic inhibition of GABA release. These alterations in GABA release were accompanied by decreased levels of the major CB1 ligand 2-arachidonoylglycerol. In contrast, GABA release from PVINs was unchanged, and the excitatory connectivity from PCs to the interneurons also underwent cell type-specific alterations. These results demonstrate that energetic charged particles at space-relevant low doses elicit surprisingly selective long-term plasticity of synaptic microcircuits in the hippocampus. The magnitude and persistent nature of these alterations in synaptic function are consistent with the observed perturbations in cognitive performance after irradiation, while the high specificity of these changes indicates that it may be possible to develop targeted therapeutic interventions to decrease the risk of adverse events during interplanetary travel.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-016-1345-3) contains supplementary material, which is available to authorized users.

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Radiation-Induced Alterations in Synaptic Neurotransmission of Dentate Granule Cells Depend on the Dose and Species of Charged Particles

Cited by 49 publications

References 53 publications

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

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

Whole-Body Exposure to²⁸Si-Radiation Dose-Dependently Disrupts Dentate Gyrus Neurogenesis and Proliferation in the Short Term and New Neuron Survival and Contextual Fear Conditioning in the Long Term

Neurophysiology of space travel: energetic solar particles cause cell type-specific plasticity of neurotransmission

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Radiation-Induced Alterations in Synaptic Neurotransmission of Dentate Granule Cells Depend on the Dose and Species of Charged Particles

Cited by 49 publications

References 53 publications

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

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

Whole-Body Exposure to28Si-Radiation Dose-Dependently Disrupts Dentate Gyrus Neurogenesis and Proliferation in the Short Term and New Neuron Survival and Contextual Fear Conditioning in the Long Term

Neurophysiology of space travel: energetic solar particles cause cell type-specific plasticity of neurotransmission

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Product

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Whole-Body Exposure to²⁸Si-Radiation Dose-Dependently Disrupts Dentate Gyrus Neurogenesis and Proliferation in the Short Term and New Neuron Survival and Contextual Fear Conditioning in the Long Term