Abstract
Nervous tissue is characterized by a tight structural association between glial cells and neurons. It is well known that glial cells support neuronal functions, but their role under pathologic conditions is less well understood. Here, we addressed this question in vivo using an experimental model of retinal ischemia and transgenic mice for glia‐specific inhibition of soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE)‐dependent exocytosis. Transgene expression reduced glutamate, but not ATP release from single Müller cells, impaired glial volume regulation under normal conditions and reduced neuronal dysfunction and death in the inner retina during the early stages of ischemia. Our study reveals that the SNARE‐dependent exocytosis in glial cells contributes to neurotoxicity during ischemia in vivo and suggests glial exocytosis as a target for therapeutic approaches.
Highlights
Neuroglial cells such as astrocytes and retinal Mu€ller cells fill the space between neurons but they represent essential partners
We used a transgenic mouse model to investigate the impact of glial sensitive factor attachment protein receptor (SNARE)-dependent exocytosis on postischemic neurodegeneration in the retina in vivo
We show that glia-specific inhibition of SNARE-dependent signaling by dnSNARE expression reduces exocytotic release of glutamate from Mu€ller cells, impairs glial volume regulation and protects retinal neurons from postischemic dysfunction and degeneration, whereas ATP release by Mu€ller cells remained unaltered
Summary
Neuroglial cells such as astrocytes and retinal Mu€ller cells fill the space between neurons but they represent essential partners Under normal conditions, they support neuronal function in different ways including potassium buffering, transmitter uptake and the provision of energy substrates (Bringmann et al, 2006; Parpura et al, 2012). They support neuronal function in different ways including potassium buffering, transmitter uptake and the provision of energy substrates (Bringmann et al, 2006; Parpura et al, 2012) Their role under pathologic conditions caused by mutations, ischemia or injuries is less well understood, they may exacerbate or mitigate neuronal damage. We studied the contribution of glial SNARE-dependent exocytosis to neurodegeneration in the retina To this end, we used an established model of transient ischemia that triggers robust neuronal dysfunction and degeneration (Osborne et al, 2004; Pannicke et al, 2014). Our results reveal that gliaspecific inhibition of SNARE-dependent signaling protects retinal neurons from dysfunction and degeneration
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