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

Abstract

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.

Keywords: Cannabinoid signaling system; GABAergic interneurons; Irradiation-induced cognitive impairments.

Fig. 1

Proton irradiation increases CB₁-sensitive GABA release. Representative tracings of CB₁BCs from control (a) and irradiated (d) mice (blue dendritic tree and soma; red axonal arbor). Insets demonstrate the characteristic spike frequency adaptation in response to a depolarizing current step (+200 pA, from −65 mV). Sholl analysis of dendritic trees revealed similar mean dendritic length between control (b) and irradiated (e) mice (length per 25 μm bin is shown as a function of distance from the cell body; two-sample Kolmogorov–Smirnov test, p > 0.1 in each bin of graded radius at 25 μm steps). The distribution of axonal varicosities was taken as the distance of each varicosity from the center of the stratum pyramidale (which is denoted as 0 on the y axis), normalized to the thickness of the layer. Pooled distributions of CB₁BC axonal arbors were similar for control (c) and irradiated (f) mice. g Representative traces of paired recordings from presynaptic CB₁BCs (top, AP) and postsynaptic PCs (bottom, IPSCs) from a control and an irradiated mouse. Fifty consecutive traces (light lines) and their averages (dark lines) are presented here and in all subsequent figures. Summary data plots demonstrate that irradiation did not affect CB₁BC to PC cell connection probability [h; numbers above bars = (# connected)/(# tested)], but did result in significant increases of euIPSC amplitudes (i) and successes of postsynaptic events (j). Ori stratum oriens, Pyr stratum pyramidale, Rad stratum radiatum. For all figures: *p < 0.05; **p <0.01; ***p < 0.005; ns not significant

Fig. 2

Reduced tonic cannabinoid signaling by irradiation. Representative traces of paired recordings from presynaptic CB₁BCs (top, AP) and postsynaptic PCs (bottom, IPSCs) in control ACSF (Control) and during application of AM251 from control group (a) and irradiated group (d). Summary of the effects of AM251 on euIPSCs in control (b) and irradiated (e) groups. Percent of presynaptic APs resulting in successful IPSCs (successes) in the postsynaptic cell in control (c) and irradiated (f) groups. Application of AM251 causes more of an increase in euIPSCs (g) and successes (h) in controls than after irradiation. After application of AM251, the amplitude of euIPSCs (i) and successes (j) are not different between groups (n = 7 pairs, 0 Gy; n = 8 pairs, 0.5 Gy)

Fig. 3

Irradiation reduced 2-arachidonoylglycerol (2-AG) levels, but not CB₁ content. a, b Super-resolution images of CB₁s of axon terminals of CB₁BCs were obtained with correlated confocal microscopy and STORM microscopy. Localization points (green dots) in the STORM images represent the position of CB₁s in the axon terminals. There are no changes in CB₁ expression in CB₁BCs as measured by bouton perimeters (c), CB₁ NLP (d), and CB₁ density (NLP/bouton perimeter) (e). Open circles represent mean values of each cell from 12 ± 3 boutons per cell normalized to the mean of control cells. Blue or red filled circles label averages of control and irradiated groups. f There were moderately strong correlations between CB₁ NLP and bouton perimeter in both groups of boutons (n = 107 and 78 boutons from control and irradiated mice, respectively). g Irradiation led to a decrease in 2-AG levels (n = 5 control, n = 4 irradiated)

Fig. 4

Irradiation did not alter GABA release from PVINs. a Representative traces of paired recordings from presynaptic PVINs (top, AP) and postsynaptic PCs (bottom, IPSCs) from a control and an irradiated mouse. Summary data plots demonstrate that irradiation did not affect PVIN to PC connection probability (b), euIPSC amplitudes (c), or successes of postsynaptic events (d)

Fig. 5

Irradiation selectively increased the connection probability between CA1 PCs and PVINs. a Representative traces of paired recordings from presynaptic PCs (top, action currents) and postsynaptic PVINs (bottom, EPSCs) from a control and an irradiated mouse. Summary data plots demonstrate that irradiation led to an increase in PC to PVIN connection probability (b), but did not affect the amplitude of euEPSCs (c) or the successes of postsynaptic events (d)