Two faces of calcium activation after optic nerve trauma: life or death of retinal ganglion cells in vivo depends on calcium dynamics

Abstract

Calcium elevations after neurotrauma are not only implicated in cell death but may contribute to adaptive plasticity. We now wished to resolve this contradiction by following calcium dynamics after optic nerve crush in vivo. Adult rats received no injury (n = 5), unilateral mild (n = 10) or moderate optic nerve crush (n = 10) (ONC), or axotomy (n = 5). Before surgery, retinal ganglion cells (RGCs) were retrogradely labelled with Oregon Green BAPTA-dextran, a fluorescent calcium marker. Calcium-related fluorescence intensity (FI) was repeatedly measured in individual RGCs in vivo using the in vivo confocal neuroimaging (ICON) method. Four different RGC types were found. Normal RGCs without FI change were found in sham rats and also in both ONC groups. RGCs with mild damage were seen only after mild ONC, showing an initial calcium depression of 26% at day 4 followed by a 169% increase 15 days after ONC. RGCs with moderate damage were found only after moderate ONC and showed calcium hypoactivation followed by a slower return toward baseline and a delayed calcium increase of 72% above baseline. Sixty to sixty-five per cent of the RGCs in both ONC groups and all RGCs in the axotomy group died within 6 days following a fast and massive calcium increase of 316% with a concomitant 156% soma size increase. In conclusion rapid calcium elevation leads to cell death, while an initial calcium depression followed by a delayed and moderate calcium hyperactivation is associated with cell survival. We propose that immediate, massive calcium activation is maladaptive whereas delayed and moderate hyperactivation of surviving cells is adaptive. Implications for pharmacotherapy are discussed.

Intravitreal Delivery of Human NgR-Fc Decoy Protein Regenerates Axons After Optic Nerve Crush and Protects Ganglion Cells in Glaucoma Models

“…It is known that cell size influences sensitivity to injury [36][37][38] and that IOP has complicated effects on cell size. [39][40][41] In our studies, the relative selectivity of axotomy and IOP for large RGC counts may reflect cell atrophy after injury with a shift from large to small diameter groups, as well as greater large cell sensitivity to injury-induced death. The pronounced NgR1(310)-Fc rescue of large RGC counts may reflect a trophic effect to increase cell size after injury, shifting smaller cells into this category.…”

In vivo visualisation of nanoparticle entry into central nervous system tissue

“…they not provide values immediately after injection), they do not provide information about the morphological distribution and they do not provide evidence regarding neuronal degeneration. ICON was established several years ago in our laboratory to investigate neurophysiological and pathophysiological issues and this method was found to be feasible for realtime observations of neuronal damage, and morphological changes such as cell size and activation changes of calcium-labelled cells (PrilloV et al 2010(PrilloV et al , 2007Sabel et al 1997;Rousseau et al 1999;Rousseau and Sabel 2001). Also, we accomplished double-labelling of healthy and degenerating retinal ganglion cells with two diVerent Xuorescent markers (PrilloV et al 2010).…”

“…the kinetic of BBB passage can be followed repetitively in living animals, 2. fast and high-frequency data collection immediately (seconds) after injection and for an extended period of time is possible, 3. parallel acquisition of data regarding kinetic and neuronal damage, 4. and morphological features of Xuorescent cells can be observed and quantiWed such as cell size (Rousseau et al 1999;Rousseau and Sabel 2001), calcium activation (PrilloV et al 2007) and extracellular/intracellular distribution of labelled nanoparticles or compounds.…”

Bernhard Sabel and ‘Residual Vision Activation Theory’: a History Spanning Three Decades

“…Repetitive stimulation may in duce 'within-system plasticity' that strengthens synaptic transmission within the partially damaged brain structures (Prilloff et al, 2007), and 'network plasticity' that improves neuronal networks in cortical and subcortical areas of both hemispheres. According to this hypothesis, cellular mechanisms of vi sual pathway restoration are similar to those that determine perceptual learning (Kasten et al, 2000).…”