Glial modulation of synaptic transmission in the retina

Abstract

Glial modulation of synaptic transmission and neuronal excitability in the mammalian retina is mediated by several mechanisms. Stimulation of glial cells evokes Ca(2+) waves, which propagate through the network of retinal astrocytes and Müller cells and result in the modulation of the activity of neighboring ganglion cells. Light-evoked spiking is enhanced in some ganglion cells and depressed in others. A facilitation or depression of light-evoked excitatory postsynaptic currents is also seen in ganglion cells following glial stimulation. In addition, stimulation of glial cells evokes a sustained hyperpolarizing current in ganglion cells which is mediated by ATP release from Müller cells and activation of neuronal A(1) adenosine receptors. Recent studies reveal that light-evoked activity in retinal neurons results in an increase in the frequency of Ca(2+) transients in Müller cells. Thus, there is two-way communication between neurons and glial cells, suggesting that glia contribute to information processing in the retina.

Fig. 1

Astrocytes and Müller cells, the two macroglial cells of the retina, are shown in this schematic of the mammalian retina. Astrocytes are confined largely to the nerve fiber layer at the vitreal (inner) border of the retina. Müller cells, specialized radial glial cells found only in the retina, span much of the retinal depth, from the vitreal border to the photoreceptor layer. The principal neurons of the retina are illustrated, as are the recording and stimulating electrodes used in experiments to monitor glial cell modulation of neuronal spiking.

Fig. 2

Propagation of Ca²⁺ waves through astrocytes and Müller cells in the rat retina. A: A Ca²⁺ wave propagates through both astrocytes and Müller cells following mechanical stimulation of an astrocyte soma (asterisk). A as well as B, D, and E are pseudocolor Ca²⁺ ratio images that show Ca²⁺ increases within glial cells. B: In the presence of 100 μM suramin, a purinergic receptor antagonist, stimulation of an astrocyte (asterisk) evokes a Ca²⁺ wave that propagates through several astrocytes but fails to propagate into neighboring Müller cells. C: Stimulation of glial cells on the retinal surface evokes ATP release, detected by the luciferin-luciferase chemiluminescence assay. Five line scans show the spatial pattern of ATP chemiluminescence at the indicated times after stimulation. D: Superfusate flow across the retinal surface (from left to right) causes asymmetric propagation of a Ca²⁺ wave. E: Addition of suramin eliminates the asymmetry despite continued superfusate flow. A, B, D, and E reproduced from Newman (2001b); C from Newman (2003).

Fig. 3

Glial modulation of light-evoked spiking in rat ganglion cells. Enhancement of neuron spiking (A) and depression of spiking (B) are illustrated in recordings from two different neurons. A frequency plot of spike activity (top trace) and Ca²⁺ levels within glial cells adjacent to the neuron (bottom trace) are shown for each trial. Arrows indicate initiation of the glial Ca²⁺ wave. The bar at the bottom shows the repetitive light stimulus that evoked neuronal spiking. Reproduced with modification from Newman and Zahs (1998).

Fig. 4

Glial release of ATP inhibits rat ganglion cells. A: Ejection of ATPγS onto the retinal surface evokes a Ca²⁺ increase in glial cells and a hyperpolarization (current-clamp recording) and an outward current (voltage-clamp recording) in a neighboring ganglion cell. B: Stimulation of glial cells with ATPγS evokes an inhibitory outward current in a ganglion cell. Addition of AOPCP, an ectonucleotidase inhibitor that blocks conversion of AMP to adenosine, reduces and slows the time course of the current. The effect is largely reversible. C: Addition of DPCPX, an A₁ adenosine receptor antagonist, abolishes the outward neuronal current evoked by ATPγS stimulation of glial cells. D: Adenosine ejection evokes a larger, shorter latency current in a neuron than does ATPγS ejection at the same retinal location. Reproduced from Newman (2003).

Fig. 5

Glial modulation of synaptic transmission by glutamate transport and release of D-serine. A: Inhibition of the glial glutamate transporter by PDC greatly increases the amplitude and duration of a light-evoked EPSC recorded from a ganglion cell in the salamander retina. Both the ON and the OFF components of the light response are potentiated. B: Addition of D-serine, an NMDA receptor coagonist, potentiates the inward current recorded from a rat ganglion cell in response to NMDA ejection. C: Addition of D-amino acid-oxidase, which degrades D-serine, reduces the inward current evoked by NMDA ejection. A reproduced from Higgs and Lukasiewicz (2002); B and C from Stevens et al. (2003).