Spontaneous patterned retinal activity and the refinement of retinal projections
Introduction
The brain contains highly ordered circuitry in which sensory inputs are organized into maps that represent different features of sensory space. One dogma of developmental neurobiology is that guidance molecules mediate initial map development, while refinement of these maps requires neural activity. This underlies many hypotheses regarding the relative contribution of activity-dependent and activity-independent factors in map formation.
In the visual system, two well-studied organizational schemes are retinotopic and eye-specific maps (see Fig. 1). In this section, we introduce these maps and provide overviews of the hypotheses regarding the relative role of activity-dependent processes and guidance molecules in their development.
Mature retinotopic maps are organized such that a visual stimulus activates neighboring retinal neurons, which in turn project to and stimulate neighboring neurons in the corresponding target structure in the brain. For example, in the superior colliculus (SC), and its non-mammalian homolog the optic tectum (OT), the nasal–temporal (N–T) axis of the retina maps to the posterior–anterior (P–A) axis of the SC, such that stimulation of the nasal retina elicits responses in posterior SC neurons, while anterior SC neurons respond to stimulation of temporal retina. The dorsal–ventral (D–V) axis of the retina maps along the lateral–medial (L–M) axis of the SC in a similar fashion. In the dorsal lateral geniculate nucleus of the thalamus (dLGN), the N–T axis of retina maps to the D–V axis of the dLGN and the D–V axis of retina maps project to the L–M axis of the dLGN (Fig. 1).
Eye-specific maps are organized such that neurons located in distinct regions in the target structure respond to visual stimuli that activate neurons in one eye or the other. For example, axons from contralateral and ipsilateral retinas make synaptic connections with neurons in separate layers within the dorsal lateral geniculate nucleus of the thalamus, each layer receiving only ipsilateral or only contralateral input. Similarly, axons from the distinct eye-specific regions in the dLGN project to distinct alternating right-eye/left-eye columns, called ocular dominance columns, in primary visual cortex. Though the retinal projections to the SC are primarily contralateral, there is an ipsilateral projection to a distinct cellular layer in the rostral part of the nucleus (Fawcett et al., 1984, O’Leary et al., 1986, Thompson and Holt, 1989).
In mammals, the precise targeting of retinal ganglion cell (RGC) axons necessary for retinotopy and eye-specific layers emerges from initially unordered projections of RGC axons within the SC and dLGN. Within the SC, all RGC axons initially extend beyond their correct topographic position, growing toward the posterior pole (Simon and O’Leary, 1992). As the axons retract, side branches form in the region that will be the topographically correct termination zone (TZ). These side branches continue to elaborate into wide, diffuse axon arbors and must further refine before becoming the tight, dense TZ seen in adults. Retinal projections to the dLGN are not thought to undergo dramatic retinotopic refinement (Huberman et al., 2005b, Sretavan et al., 1988).
Within the dLGN, RGC axons from both eyes are initially intermixed (Godement et al., 1984, Linden et al., 1981, Penn et al., 1998, Shatz and Kirkwood, 1984). Shortly after RGC axons have reached the dLGN, intraocular injection of an anterograde tracer into the ipsilateral eye labels a large region of the dLGN, while tracer injection into the contralateral eye results in a uniform labeling of the entire dLGN. Later, contralaterally projecting axons are excluded from the region occupied by ipsilaterally projecting axons. The changes in axonal morphology that may underlie this segregation have been studied in the cat, where, after arriving in the dLGN, small side branches of retinal axons begin to form off the main axon shaft (Sretavan and Shatz, 1986). Throughout development, a dense axonal arbor begins to form in the correct eye-specific layer, while incorrect branches are eliminated. This process of elaboration and retraction eventually results in the segregation of afferents from each eye into separate layers within the dLGN. A similar process underlies eye-specific segregation of retinal projections to the SC (Fawcett et al., 1984, O’Leary et al., 1986, Thompson and Holt, 1989). A recent study suggests that in fetal primates, eye-specific layers form before the analogous period of synaptic refinement described above (Huberman et al., 2005a).
Two types of mechanisms have been proposed to underlie map formation: matching molecular cues; and activity-dependent synaptic rearrangements. The concept that gradients of molecular cues specify the correct topographic location of axonal termination within a target structure was first proposed by Roger Sperry as a chemoaffinity hypothesis (Sperry, 1963). Sperry hypothesized that molecular gradients within the retina and tectum give each cell a unique chemical tag or identification. These chemical tags specify which retinal and tectal cells should form synapses with each other. This hypothesis can be applied to eye-specific layers, whereby each RGC expresses a chemical tag corresponding to its eye of origin that must match with a chemical tag for the correct eye layer within the dLGN.
Most activity-dependent mechanisms of map formation have been based on Hebb's postulate (1949), which states that synapses are strengthened when the pre- and post-synaptic cells are simultaneously active (Zhang and Poo, 2001). Hebb's postulate has been expanded to include the converse: asynchronously active synapses are weakened and eventually eliminated. Models based on Hebb's postulate predict that activity plays an “instructive role,” meaning that all of the information required to drive the refinement is contained in the activity patterns. In this scenario, activity that drives the neural rearrangements that underlie retinotopic refinement would contain information about the distance between two RGCs. Neighboring neurons are characterized by temporally correlated firing of action potentials, with the amount of correlation decreasing as a function of distance between the RGCs. Furthermore, activity that drives eye-specific refinement would contain information about the eye of origin, e.g., activity from neighboring RGCs originating in one retina is more correlated than activity between retinas.
Does the visual system generate the types of activity that could drive activity-dependent refinement? In amphibians and fish, the retina is responsive to light before its projections reach their target structures in the brain, suggesting that vision could provide the activity necessary for refinement. In mammals, the refinement of retinotopic retinocollicular maps and eye-specific retinogeniculate maps, however, occurs prior to the presence of functional photoreceptors. Though there are no visually evoked responses during this time, spontaneous waves of depolarization, termed retinal waves, traverse the retina (for recent review, see Firth et al., 2005). Retinal waves are composed of bursts of action potentials that correlate the firing of neighboring RGCs, while the firing of more distant RGCs is less correlated (Demas et al., 2003a, McLaughlin et al., 2003b, Meister et al., 1991, Wong et al., 1993). This change in the amount of correlation as a function of distance between cells may be appropriate for establishing retinotopic maps. In addition, individual RGCs participate in waves infrequently (firing for approximately 5 s and then silent for 1–2 min). Thus, there is a low probability that RGCs from each eye will fire simultaneously. These strong intra-retinal correlations combined with weak inter-retinal correlations may be appropriate for driving eye-specific segregation.
Here we review evidence that elucidates the relative role of molecular cues and patterned spontaneous retinal activity in the refinement of retinotopic maps in retinocollicular projections and eye-specific refinement of retinogeniculate projections. First, we review the mechanisms that underlie the generation of retinal waves. Second, we explore how manipulations that alter retinal wave activity influence the development of retinal projections. Third, we will review the role of guidance molecules and signaling cascade molecules in the refinement of those projections. Last, we propose that there are several mechanisms by which patterned activity and guidance molecules interact and that a synergism of mechanisms may be the key to understanding the refinement of connections within the developing visual system.
Section snippets
The cellular basis of spatiotemporal patterns of retinal waves
To test the hypothesis that retinal waves contain all the information to drive map refinement, there is an ongoing search to develop manipulations that alter specific features of the firing patterns. Hence, identifying the cell classes and mechanisms involved in generating waves is critical. The synaptic circuits that generate retinal waves have been described in several vertebrate species, including ferret, cat, mouse, rabbit, turtle, and chick (for reviews see Catsicas et al., 1998, Feller,
Role for neural activity in the formation of retinotopic and eye-specific maps
Prior to eye-opening, retinal axons establish synaptic connections with their targets in the brain. These connections are organized within the target tissue in a fashion that is dictated by the relative spatial location of their origin in the retina. The temporal coincidence of retinal waves and establishment of both retinotopic and eye-specific maps has led to the hypothesis that the activity induced by retinal waves is essential for correctly establishing these connections. In this section we
Markers that specify retinotopic location
Retinotopic refinement within the SC, or its non-mammalian homolog the optic tectum, is often used as a classic example of the ability of gradients of guidance molecules to bring about the precise targeting of axons (for reviews, see Flanagan and Vanderhaeghen, 1998, Kullander and Klein, 2002, McLaughlin et al., 2003a, Ruthazer and Cline, 2004). In fact, it was based upon experiments in this system that Sperry first proposed his chemoaffinity hypothesis, which states that each topographic
Interactions between activity and guidance molecules
Whether activity or guidance molecules are responsible the formation of maps within the visual system has been debated for many years. While in the past many scientists have taken either one side or the other in the debate, recently the two sides have begun to reach a middle ground, acknowledging that both activity and molecular cues may be responsible for establishing maps. Now the debate is changing from whether activity or molecular cues establish maps to what the relative contributions of
Linking patterned activity to axonal rearrangements
We have reviewed evidence that some features of retinal waves are necessary for axonal rearrangements during retinotopic and eye-specific refinement. However, the mechanisms by which action potentials result in these axonal rearrangements have not been elucidated. We now discuss evidence for three classes of mechanisms involved in activity-dependent synaptic refinement: (1) Hebbian-based synaptic competition; (2) activity-dependent gene transcription; and (3) intracellular signaling cascades.
Conclusions
How the connectivity of the visual system emerges during development remains one of the great mysteries of developmental neuroscience. Classically, the mechanisms that underlie the establishment of sensory maps have been categorized as activity-dependent or activity-independent. If any progress has been made in the last few years, it is that this distinction may no longer be appropriate. There is ample evidence that both guidance molecules and spontaneous activity are critical for driving map
Acknowledgment
This work was supported in part by a McKnight Scholars Fund, and the National Institute of Health (grant no. NS13528).
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