Neuropeptide Y Inhibits Hypotonic Glial Cell Swelling in the Postischemic Rat Retina via Glutamatergic Neuron–to–Glia Signaling

Abstract

Abstract: : Purpose: Various different ocular diseases are accompanied by the development of retinal edema which is implicated in causing photoreceptor cell death after ischemia or trauma. Retinal edema has been suggested to be caused by both opening of blood–retinal barriers (extracellular edema) and glial cell swelling (cytotoxic edema). While the regulation of blood–retinal barriers is a focus of research since many years, almost nothing is known about the mechanisms and modulation of retinal glial cell swelling by neurotransmitters. Recently, we suggested a K⁺ channel– and aquaporin–dependent mechanism which may be implicated in glial cell swelling in the postischemic rat retina (Pannicke et al., 2004, Mol. Cell. Neurosci., 26:493–502). Since neuropeptide Y (NPY) is the most abundant neuropeptide in the brain, and is also released in the retina in response to light, we investigated the effect of this peptide on Muller cell swelling. Methods:Transient retinal ischemia was induced in one eye of adult rats by elevating the intraocular pressure for 60 min. Three days after ischemia, the alteration of the cross–sectional area of Muller cell somata upon hypotonic stress (a situation resembling hypoxia–induced cytotoxic edema in the brain) was recorded in acutely isolated retinal slices. Results: NPY dose–dependently inhibited the glial cell swelling evoked by hypotonic challenge, with a half–maximal effect at ∼5 nM. The effect of NPY was mimicked by a selective Y1 receptor agonist, while selective agonists of Y2 and Y5 receptors were without effect. The effect is mediated by NPY–evoked activation of retinal neurons, and calcium–dependent release of glutamate. Apparently, glutamate stimulates mGluRs on Muller cells which subsequently release purinergic agonists. Autocrine stimulation of A1 receptors by adenosine inhibits the hypotonic swelling of Muller cells. Conclusions: The data suggest that NPY inhibits hypotonic glial cell swelling by activation of neuronal Y1 receptors; this effect is mediated by subsequent stimulation of glutamatergic and purinergic receptors on Muller cells. The results may have importance for the understanding of light–induced cell volume regulation in the retina, as well as for the development of new therapeutic strategies for inhibition of postischemic and posttraumatic glial cell swelling.

Keywords: ischemia • neuropeptides • Muller cells