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Biomedical subjects

R O Wong

Publications and source records attributed to R O Wong.

At least 19 recordsLinked to original sources
PubMed2001

Mechanisms underlying developmental changes in the firing patterns of ON and OFF retinal ganglion cells during refinement of their central projections.

Patterned neuronal activity is implicated in the refinement of connectivity during development. Calcium-imaging studies of the immature ferret visual system demonstrated previously that functionally separate ON and OFF retinal ganglion cells (RGCs) develop distinct temporal patterns of spontaneous activity as their axonal projections undergo refinement. OFF RGCs become spontaneously more active compared with ON cells, resulting in a decrease in synchronous activity between these cell types. This change in ON and OFF activity patterns is suitable for driving the activity-dependent refinement of their axonal projections. Here, we used whole-cell and perforated-patch recording techniques to elucidate the mechanisms that underlie the developmental alteration in the ON and OFF RGC activity patterns. First, we show that before the refinement period, ON and OFF RGCs have similar spike patterns; however, during the period of segregation, OFF RGCs demonstrate significantly higher spike rates relative to ON cells. With increasing age, OFF cells require less depolarization to reach their action potential threshold and fire more spikes in response to current injection compared with ON cells. In addition, spontaneous postsynaptic currents and potentials are greater in magnitude in OFF cells than ON cells. In contrast, before axonal refinement, there are no differences in the intrinsic excitability or synaptic drive onto ON and OFF cells. Together, our results show that developmental changes in ON and OFF RGC excitability and in the strength of their synaptic drives act together to reshape the spike patterns of these cells in a manner appropriate for the refinement of their connectivity.

Action Potentials↗
PubMed2001

Development of retinal ganglion cell structure and function.

In this review, we summarize the main stages of structural and functional development of retinal ganglion cells (RGCs). We first consider the various mechanisms that are involved in restructuring of dendritic trees. To date, many mechanisms have been implicated including target-dependent factors, interactions from neighboring RGCs, and afferent signaling. We also review recent evidence showing how rapidly such dendritic remodeling might occur, along with the intracellular signaling pathways underlying these rearrangements. Concurrent with such structural changes, the functional responses of RGCs also alter during maturation, from sub-threshold firing to reliable spiking patterns. Here we consider the development of intrinsic membrane properties and how they might contribute to the spontaneous firing patterns observed before the onset of vision. We then review the mechanisms by which this spontaneous activity becomes correlated across neighboring RGCs to form waves of activity. Finally, the relative importance of spontaneous versus light-evoked activity is discussed in relation to the emergence of mature receptive field properties.

Animals↗
PubMed2001

Two modes of radial migration in early development of the cerebral cortex.

Layer formation in the developing cerebral cortex requires the movement of neurons from their site of origin to their final laminar position. We demonstrate, using time-lapse imaging of acute cortical slices, that two distinct forms of cell movement, locomotion and somal translocation, are responsible for the radial migration of cortical neurons. These modes are distinguished by their dynamic properties and morphological features. Locomotion and translocation are not cell-type specific; although at early ages some cells may move by translocation only, locomoting cells also translocate once their leading process reaches the marginal zone. The existence of two modes of radial migration may account for the differential effects of certain genetic mutations on cortical development.

Animals↗
PubMed2001

Changing specificity of neurotransmitter regulation of rapid dendritic remodeling during synaptogenesis.

Wiring the developing nervous system requires appropriate contact between presynaptic axons and postsynaptic dendrites. Rapid movements of filopodia-like structures on immature dendrites are thought to facilitate initial synaptogenic contact with axons. Here we show that not only can different forms of neurotransmission regulate dendritic filopodial motility, but they do so in a developmentally regulated manner, suggestive of a specific relationship between the action of a neurotransmitter and the corresponding type of synapse being formed.

Acetylcholine↗
PubMed2001

Cell-type specific dendritic contacts between retinal ganglion cells during development.

The extent of a neuron's dendritic field defines the region within which information is processed. The dendritic fields of functionally distinct ON and OFF center retinal ganglion cells (RGCs) form separate mosaics across the retina. Within each mosaic, neighboring dendritic fields overlap by a constant amount, sampling the visual field with the appropriate coverage. Contact-mediated lateral inhibition between neighboring RGCs has long been thought to regulate both the extent and overlap of dendritic fields during development. Here we show that dendro-dendritic contact exists between developing RGCs and occurs in a manner that would regulate the formation of ON and OFF mosaics separately. Dye-filled neighboring ON and OFF ferret alpha RGCs were reconstructed using multiphoton microscopy. At all neonatal ages examined, we observed dendro-dendritic contacts between RGCs of the same sign (ON/ON; OFF/OFF), but never between cells of opposite signs (ON/OFF). Terminal dendrites of one cell often touched a dendrite of its neighbor as they intersected. In some instances, the distal dendrite of one cell formed a fascicle with the proximal process of its neighbor. Alpha cells did not form contacts with neighboring beta cells of the same sign. Together, these observations suggest that dendro-dendritic contact between RGCs is cell-type specific. Dendritic contacts were observed even before the alpha cell arbors were completely stratified, suggesting that cell-cell recognition may take place early in their development. For each cell type, the relative overlap of dendritic fields was constant with age, despite a two-fold increase in field area. We suggest that dendro-dendritic contacts may be sites of intercellular signaling that could regulate local extension of dendrites to maintain the relative overlap of RGCs within a mosaic during development.

Animals↗
PubMed2000

Rapid dendritic remodeling in the developing retina: dependence on neurotransmission and reciprocal regulation by Rac and Rho.

We demonstrate that within the intact and spontaneously active retina, dendritic processes of ganglion cells exhibit rapid and extensive movements during the period of synaptogenesis. Marked restructuring occurs in seconds, but structural changes are relatively balanced across the dendritic arbor, maintaining overall arbor size and complexity over hours. Dendritic motility is regulated by spontaneous glutamatergic transmission. Both the rate and extent of the movements are decreased by antagonists to NMDA and non-NMDA glutamate receptors but are unaffected by tetrodotoxin, a sodium channel blocker. The dendritic movements are actin dependent and are controlled by the Rho family of small GTPases. Transfection of dominant-negative and constitutively active mutants into ganglion cells showed that Rac and Rho exert reciprocal effects on motility. We suggest that the Rho family of small GTPases could integrate activity-dependent and -independent signals from afferents, thereby adjusting target motility and maximizing the chance for initial contact and subsequent synaptogenesis.

2-Amino-5-phosphonovalerate↗
PubMed2000

Distinct ionotropic GABA receptors mediate presynaptic and postsynaptic inhibition in retinal bipolar cells.

Ionotropic GABA receptors can mediate presynaptic and postsynaptic inhibition. We assessed the contributions of GABA(A) and GABA(C) receptors to inhibition at the dendrites and axon terminals of ferret retinal bipolar cells by recording currents evoked by focal application of GABA in the retinal slice. Currents elicited at the dendrites were mediated predominantly by GABA(A) receptors, whereas responses evoked at the terminals had GABA(A) and GABA(C) components. The ratio of GABA(C) to GABA(A) (GABA(C):GABA(A)) was highest in rod bipolar cell terminals and variable among cone bipolars, but generally was lower in OFF than in ON classes. Our results also suggest that the GABA(C):GABA(A) could influence the time course of responses. Currents evoked at the terminals decayed slowly in cell types for which the GABA(C):GABA(A) was high, but decayed relatively rapidly in cells for which this ratio was low. Immunohistochemical studies corroborated our physiological results. GABA(A) beta2/3 subunit immunoreactivity was intense in the outer and inner plexiform layers (OPL and IPL, respectively). GABA(C) rho subunit labeling was weak in the OPL but strong in the IPL in which puncta colocalized with terminals of rod bipolars immunoreactive for protein kinase C and of cone bipolars immunoreactive for calbindin or recoverin. These data demonstrate that GABA(A) receptors mediate GABAergic inhibition on bipolar cell dendrites in the OPL, that GABA(A) and GABA(C) receptors mediate inhibition on axon terminals in the IPL, and that the GABA(C):GABA(A) on the terminals may tune the response characteristics of the bipolar cell.

Animals↗
PubMed2000

Developmental changes in the neurotransmitter regulation of correlated spontaneous retinal activity.

Synchronized spontaneous rhythmic activity is a feature common to many parts of the developing nervous system. In the early visual system, before vision, developing circuits in the retina generate synchronized patterns of bursting activity that contain information useful for patterning connections between retinal ganglion cells and their central targets. However, how developing retinal circuits generate and regulate these spontaneous activity patterns is still incompletely understood. Here we show that in developing retinal circuits, the nature of excitatory neurotransmission driving correlated bursting activity in ganglion cells is not fixed but undergoes a developmental shift from cholinergic to glutamatergic transmission. In addition, we show that this shift occurs as presynaptic glutamatergic bipolar cells form functional connections onto the ganglion cells, implicating the role of bipolar cells in providing endogenous drive to bursting activity later in development. This transition coincides with the period when subsets of ganglion cells (On and Off cells) develop distinct activity patterns that are thought to underlie the refinement of their connectivity with their central targets. Here, our results suggest that the differences in activity patterns of On and Off ganglion cells may be conferred by differential synaptic drive from On and Off bipolar cells, respectively. Taken together, our results suggest that the regulation of patterned spontaneous activity by neurotransmitters undergoes systematic change as new cellular elements are added to developing circuits and also that these new elements can help specify distinct activity patterns appropriate for shaping connectivity patterns at later ages.

2-Amino-5-phosphonovalerate↗
PubMed2000

Multicolor "DiOlistic" labeling of the nervous system using lipophilic dye combinations.

We describe a technique for rapid labeling of a large number of cells in the nervous system with many different colors. By delivering lipophilic dye-coated particles to neuronal preparations with a "gene gun," individual neurons and glia whose membranes are contacted by the particles are quickly labeled. Using particles that are each coated with different combinations of various lipophilic dyes, many cells within a complex neuronal network can be simultaneously labeled with a wide variety of colors. This approach is most effective in living material but also labels previously fixed material. In living material, labeled neurons continue to show normal synaptic responses and undergo dendritic remodeling. This technique is thus useful for studying structural plasticity of neuronal circuits in living preparations. In addition, the Golgi-like labeling of neurons with many different colors provides a novel way to study neuronal connectivity.

Animals↗
PubMed2000

Rapid dendritic movements during synapse formation and rearrangement.

Major technical advances in the imaging of live cells have led to a recent flurry of studies demonstrating how dendrites remodel dynamically during development. Taken together with our current understanding of axonal development, these studies help provide a more unified picture of how neural circuits might be formed altered or maintained throughout life.

Animals↗
PubMed1999

Retinal waves and visual system development.

Many pathways in the developing visual system are restructured and become highly organized even before vision occurs. Yet the developmental processes underlying the remodeling of visual connectivity are crucially dependent on retinal activity. Surprisingly, the immature and light-insensitive retina spontaneously generates a pattern of rhythmic bursting activity during the period when the connectivity patterns of retinal ganglion cells are shaped. Spatially, the activity is seen to spread across the retina in the form of waves that bring into synchrony the bursts of neighboring cells. Waves are present in the developing retina of higher and lower vertebrates, which suggests that this form of activity may be a common and fundamental mechanism employed in the activity-dependent refinement of early patterns of visual connections. Unraveling the cues encoded by the waves promises to provide important insights into how interactions driven by specific patterns of activity could lead to the modification of connectivity during development.

Animals↗
PubMed1998

Developmentally regulated spontaneous activity in the embryonic chick retina.

Even before birth and the onset of sensory experience, neural activity plays an important role in shaping the vertebrate nervous system. In the embryonic chick visual system, activity in the retina before vision has been implicated in the refinement of retinotopic maps, the elimination of transient projections, and the survival of a full complement of neurons. In this study, we report the detection of a physiological substrate for these phenomena: waves of spontaneous activity in the ganglion cell layer of the embryonic chick retina. The activity is robust and highly patterned, taking the form of large amplitude, rhythmic, and wide-ranging waves of excitation that propagate across the retina. Activity waves are most prominent and organized between embryonic days 13-18, coinciding with the developmental period during which retinal axons refine their connections in their targets. The spatial and temporal features of the patterns observed are consistent with the role of activity patterns in shaping eye-specific projections and retinotopic maps but inconsistent with the hypothesis that they specify lamina-specific projections in the tectum. Antagonists of glutamatergic and glycinergic transmission and of gap junctional communication suppress spontaneous activity, whereas antagonists to GABAergic transmission potentiate it. Based on these results, we propose that spontaneous activity in the ganglion cells is regulated by chemical inputs from both bipolar and amacrine cells and by gap junctional coupling involving ganglion cells.

Animals↗
PubMed1998

Age-dependent and cell class-specific modulation of retinal ganglion cell bursting activity by GABA.

Competition for postsynaptic targets during development is thought to be driven by differences in temporal patterns of neuronal activity. In the ferret visual system, retinal ganglion cells that are responsive either to the onset (On) or to the offset (Off) of light exhibit similar patterns of spontaneous bursting activity early in development but later develop different bursting rhythms during the period when their axonal arbors segregate to occupy spatially distinct regions in the dorsal lateral geniculate nucleus. Here, we demonstrate that GABAergic transmission plays an important, although not exclusive, role in regulating the bursting patterns of morphologically identified On and Off ganglion cells. During the first and second postnatal weeks, blocking GABAA receptors leads to a decrease in the bursting activity of all ganglion cells, suggesting that GABA potentiates activity at the early ages. Subsequently, during the period of On-Off segregation in the geniculate nucleus, GABA suppresses ganglion cell bursting activity. In particular, On ganglion cells show significantly higher bursting rates when GABAergic transmission is blocked, but the bursting rates of Off ganglion cells are not affected systematically. Thus, developmental differences in the bursting rates of On and Off ganglion cells emerge as GABA becomes inhibitory and as it consistently and more strongly inhibits On compared with Off ganglion cells. Because in many parts of the CNS GABAergic circuits appear early in development, our results also implicate a potentially important and possibly general role for local inhibitory interneurons in creating distinct temporal patterns of presynaptic activity that are specific to each developmental period.

Aging↗
PubMed1998

Calcium imaging and multielectrode recordings of global patterns of activity in the developing nervous system.

Complex but coordinated interactions involving ensembles of neuronal cells result in the accurate processing of information in the adult central nervous system. However, recent studies monitoring the global patterns of activity of neuronal populations have demonstrated that immature neurons also interact to produce coordinated patterns of activity during the early stages of development. In particular, these patterns of coordinated activity occur during the period when neuronal connections are established, thus leading us to believe that such activity patterns might underlie the precision to which many neural pathways are wired up. Multielectrode recording and calcium imaging are two of the techniques that have been instrumental in revealing the spatial and temporal properties of the coordinated activity of developing neural networks in vitro. While multielectrode arrays measure the action potential activity of the cells, calcium imaging permits changes in intracellular calcium levels to be monitored over time. Both techniques have been used successfully to monitor the activity of cellular networks in culture, but they have also been applied in assessing the patterns of activity in intact or semi-intact pieces of neural tissues, such as the developing retina, neocortex and spinal cord. More recently, it has also been possible to correlate the structure and function of the cellular components of the networks by combining intracellular dye filling with the multineuronal recordings. In this review, brief descriptions and the applications of the two techniques will be presented, and the advantages and limitations of multielectrode array will be compared with that of calcium imaging using recordings of the developing mammalian retina as the primary example.

Action Potentials↗
PubMed1996

Changing patterns of spontaneous bursting activity of on and off retinal ganglion cells during development.

In adult ferrets, retinal ganglion cells (RGCs) responsive to increased (On) or decreased (Off) illumination convey information to different cellular layers of the dorsal lateral geniculate nucleus (dLGN). These dLGN sublaminae emerge during development when RGCs are found to undergo correlated spontaneous bursting activity. Using Ca2+ imaging and intracellular dye-filling techniques, we demonstrate here that in ferret neonates, morphologically identified On and Off beta RGCs have similar burst frequencies prior to the segregation of their inputs in the dLGN, but during the segregation period, they develop distinct burst frequencies. Although the bursts of On cells and Off cells occur synchronously, On cells burst only 25%-35% of the time that Off cells do. This change in the temporal bursting patterns of On and Off RGCs may underlie the segregation of their inputs on dLGN neurons.

Age Factors↗