Retinal waves: mechanisms and function in visual system development
Introduction
Periodic spontaneous activity is found in many parts of the developing central nervous system including the spinal cord, cortex, hippocampus and retina (reviewed in [1]). There is growing evidence that these early spontaneous depolarizations and increases in intracellular calcium play a crucial role in driving many aspects of development, including axon guidance, establishment of cell phenotype, local circuit formation and establishment of sensory maps. This phenomenon has been studied extensively in the retina. During a developmental period prior to vision, when there is tremendous sculpting of circuits within the visual system, immature retinal circuits spontaneously generate propagating bursts of action potentials termed retinal waves. Manipulations of retinal waves affect several features of early visual circuits, indicating that spontaneous retinal activity plays a critical role in driving activity-dependent processes during visual system development [2], [3].
It has been more than two decades since the phenomenon of neuronal retinal waves was first described in the developing mammalian retina (for complete references see [4]). Spontaneous bursts of action potentials that occur roughly once per minute were recorded in the neonatal rabbit retina and were blocked by nicotinic acetylcholine receptor (nAChR) antagonists indicating a role for early cholinergic circuits in driving the activity. Over 10 years later, in vivo recordings in fetal rat pups revealed that neighboring retinal ganglion cells (RGCs) fire correlated bursts of action potentials. Multielectrode array experiments showed these periodic correlated bursts of action potentials propagate like waves across the ganglion cell layer of ferret retinas. Calcium imaging demonstrated correlated calcium transients also propagate across the ganglion cell layer of the retina in a wave-like manner. Simultaneous electrophysiological recordings and calcium imaging experiments indicate that these calcium transients reflect the calcium influx during depolarization and not release from intracellular stores. Therefore, retinal waves recorded by calcium imaging correspond to waves of depolarization.
Calcium imaging enables the pattern of spontaneous activity to be analyzed over much larger regions of the retina than recorded with the multielectrode recordings. This has allowed investigators to define several spatiotemporal properties of waves (Fig. 1, [5], [6], [7]). Waves initiate at random locations and propagate over a finite distance of the retina. The domain, defined by the propagation boundaries for individual waves, is determined in part by a refractory period—a period of time lasting 40–60 s following a wave during which time subsequent retinal waves cannot propagate within the same area of the retina.
A biophysical model of the developing retina predicts that this refractory period dictates several features of retinal waves, including the velocity and the periodicity of retinal waves [6], [8]. Velocity is defined as the distance between wave fronts per unit time, and the periodicity is the average time interval between wave-induced calcium transients or depolarizations recorded in a particular neuron in the ganglion cell layer. According to this model, wave velocity is determined by the density of refractory cells—if there is a low density of refractory cells, waves propagate quickly and if there is a high density, waves propagate more slowly. As the density of refractory cells goes above a threshold, waves are prevented from propagating at all, and therefore a high density of refractory cells defines the boundaries of waves. This also means that shortening the length of the refractory period will increase the velocity of waves. The relationship between the refractory period and wave periodicity is more straightforward—a given retinal neuron cannot participate in sequential waves at intervals shorter than the refractory period. Hence, a major prediction of the model is that the same manipulations that increase wave velocity should also decrease the interval between retinal waves.
Here, we review current insights into the mechanisms underlying retinal wave generation and a role for retinal waves in driving refinement of circuits involving RGCs. (Note, we focus primarily on mammalian retinal waves, which may have distinctly different mechanisms and functions from the non-mammalian retina.) Although progress has been made in defining the cell types that are involved in generating retinal waves [2], [3], [4], several general questions remain regarding the cellular basis of this patterned activity. We will explore the mechanisms that determine the velocity and periodicity of retinal waves because these properties dictate the spatiotemporal properties of the correlated activity that drive downstream developmental processes. Velocity determines the temporal structure of correlations between the neighboring RGCs that may be critical for retinotopic refinement. The periodicity of action potential-driven calcium transients may be critical for the “frequency tuning” of calcium transients that drive a variety of early developmental events (see Spitzer in this issue). We also review the experiments that address whether these correlated firing patterns associated with retinal waves are critical for refinement of retinal projections to the dorsal lateral geniculate nucleus (dLGN) of the thalmus and the superior colliculus (SC) as well as the development of the retina itself.
Section snippets
Cellular basis of retinal wave propagation and periodicity
What determines the velocity of retinal waves? Retinal waves propagate in a saltatory manner, with an average velocity of 100–300 μm/s [4]. This ‘intermediate’ speed of propagating neural activity is rarely seen in the nervous system. This velocity by far exceeds the rate of extracellular diffusion of excitatory substances, such as those underlying spreading depression, a well-characterized phenomenon in the adult retina [9]. In addition, the observed propagation velocity is significantly slower
A role for retinal waves in visual system development
Many features of the retinal waves, as characterized by calcium imaging and extracellular multielectrode array recordings, suggest that they may drive early activity-dependent formation of functional circuits (reviewed in [2]). First, retinal waves are present during the period when the inner plexiform layer (IPL) is stratifying into the five layers seen in the adult retina and there is extensive refinement of retinal axons in their central visual targets, the dLGN and SC. Second, retinal waves
Acknowledgements
Supported in part by the Whitehall Foundation, March of Dimes, McKnight Scholars Fund, and the National Institute of Health (grant no. NS13528-01A1). Thanks to C.L. Torborg, T. del Rio and K.A. Hansen for their critical comments on the manuscript.
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