Electrical brain stimulation induces dendritic stripping but improves survival of silent neurons after optic nerve damage

Abstract

Repetitive transorbital alternating current stimulation (rtACS) improves vision in patients with chronic visual impairments and an acute treatment increased survival of retinal neurons after optic nerve crush (ONC) in rodent models of visual system injury. However, despite this protection no functional recovery could be detected in rats, which was interpreted as evidence of “silent survivor” cells. We now analysed the mechanisms underlying this “silent survival” effect. Using in vivo microscopy of the retina we investigated the survival and morphology of fluorescent neurons before and after ONC in animals receiving rtACS or sham treatment. One week after the crush, more neurons survived in the rtACS-treated group compared to sham-treated controls. In vivo imaging further revealed that in the initial post-ONC period, rtACS induced dendritic pruning in surviving neurons. In contrast, dendrites in untreated retinae degenerated slowly after the axonal trauma and neurons died. The complete loss of visual evoked potentials supports the hypothesis that cell signalling is abolished in the surviving neurons. Despite this evidence of “silencing”, intracellular free calcium imaging showed that the cells were still viable. We propose that early after trauma, complete dendritic stripping following rtACS protects neurons from excitotoxic cell death by silencing them.

Immune evasion by cancer stem cells

“…In contrast to human HLA-G, the murine homolog, Qa-2, has been reported to be an immunogenic molecule and contribute to tumor rejection [ 109 ]. In murine CD44 + /CD24 − breast CSCs, Qa-2 expression was abrogated, possibly by the Src signaling pathway, whereas Src inhibitor treatment suppressed the CSC properties of breast cancer cells and restored Qa-2 expression [ 110 ]. Moreover, Qa-2 overexpression suppressed breast cancer growth and metastasis [ 110 ].…”

“…In murine CD44 + /CD24 − breast CSCs, Qa-2 expression was abrogated, possibly by the Src signaling pathway, whereas Src inhibitor treatment suppressed the CSC properties of breast cancer cells and restored Qa-2 expression [ 110 ]. Moreover, Qa-2 overexpression suppressed breast cancer growth and metastasis [ 110 ]. Therefore, caution is needed when interpreting the Qa-2 and HLA-G data obtained from mouse studies.…”

Neuroprotective strategies for retinal disease

“…RGC death due to ischemia from elevated IOP is also delayed using transcorneal electrical stimulation with 1.2x greater RGC density and ERG amplitudes 2.2x greater (Wang et al, 2011). Furthermore, treating with repetitive transorbital alternating current stimulation following optic nerve crush in rats induced dendritic pruning in surviving neurons, potentially protecting them from excitotoxicity, although they did not produce functional signals (Henrich Noack et al, 2017). In a model of nonarteritic ischemic optic neuropathy, electrical stimulation sustained RGC function measured by scotopic threshold response with 1.9x greater amplitudes than sham and 1.5x greater RGC density (Osako et al, 2013).…”

“…Whether these results could be improved by treating earlier, or optimizing the stimulation paradigms is not known. Additionally, some of these benefits could be produced by activation of brain regions (Bola et al, 2014; Henrich Noack et al, 2013a, 2017; Sergeeva et al, 2015).…”

Electrical Stimulation Promotes Stem Cell Neural Differentiation in Tissue Engineering

“…Repetitive transorbital AC stimulation was used to treat mice with optic nerve injury. After treatment, many large neurons survived with moderate dendritic shrinkage [ 54 ].…”