Mechanisms and functional consequences of glial signaling in the retina.

Abstract

Twenty years ago, glia were viewed as passive support cells for neurons. Since then, experiments have shown that glial cells have their own form of excitability with precise intracellular spatiotemporal dynamics, intercellular communication among themselves, a bidirectional dialog with neurons and synapses, and a key role in mediating blood flow changes in response to neuronal activity. Most of these experiments have been conducted in brain regions such as hippocampus, cortex, hypothalamus, and cerebellum. However, as work from our laboratory has shown, the mammalian retina is also an excellent preparation to study the active functions of glial cells. Here, we describe two forms of active glial signaling in the retina. First, we tested the hypothesis that glial cells modulate synaptic activity in the retina. We measured synaptic strength by evoking excitatory postsynaptic currents (EPSCs) in ganglion cells with either light or an electrical stimulus. We then excited glial cells through several methods, including agonist ejection, photolysis of caged Ca2+, and depolarization. The amplitude of the synaptic currents was altered by some, but not all, of these glial stimuli, leaving us unable to draw a definitive conclusion as to whether glial excitation alone is sufficient to modulate synaptic transmission in the retina. Second, we characterized spontaneous intercellular glial Ca2+ waves in the retina. Glial cell excitability takes the form of transient intracellular Ca2+ elevations. One of the first recognized active properties of glia was their ability to propagate these Ca2+ elevations from cell to cell in a wave-like pattern. In most previous experiments, glial Ca2+ waves were initiated by an experimenter-driven stimulus, raising doubts about whether these waves occurred naturally in the organism. We demonstrate here that these waves occur spontaneously both in intact tissue and in vivo, and that the rate of spontaneous wave generation increases as animals age. These spontaneous waves propagate by glial release of ATP and activation of ATP receptors on neighboring cells. Finally, spontaneous waves cause changes in blood vessel diameter. This is the first demonstration of a functional effect of spontaneous intercellular glial signaling. These results suggest a functional role for glial cell signaling in the retina and raise the possibility that glial signaling may actively participate in the aging of the nervous system.