Swelling of Muller cells induced by AP3 and glutamate transport substrates in rat retina

Previous studies have shown that a single systemic injection of 2- amino-3-phosphonopropionate (AP3), an agonist/antagonist at metabotropic glutamate receptors, produces marked swelling of rodent Muller cells. To investigate the effects of AP3 on Muller cells, we used in vitro retinal segments prepared from 30 day old rats. Incubation with AP3 for 1 h or more caused severe swelling of Muller cells with the appearance of mitotic cellular profiles in the outer nuclear layer. The Muller cell swelling was mimicked by substrates for glutamate transporters, suggesting that AP3 may produce its effects via transport into glial cells. To determine whether AP3 is a substrate for glutamate transporters, we studied cultured rat hippocampal astrocytes using whole-cell patch clamp recordings. In hippocampal astrocytes, AP3 activated currents via an Na ⁺- dependent glutamate transporter. Consistent with this, substitution of extracellular sodium with choline blocked Muller cell swelling in the rat retina. These results indicate that the acute glial swelling produced by AP3 results primarily from a fluid shift that accompanies the transport of AP3 and sodium into Muller cells.