Biomedical subjects

Stephen J Eglen

Publications and source records attributed to Stephen J Eglen.

10 recordsLinked to original sources

PubMed2006

Development of regular cellular spacing in the retina: theoretical models.

During development of the nervous system, neurons should be appropriately positioned to enable them to make the right functional contacts. Neurons do not immediately migrate to their correct location, but instead regular arrangements gradually emerge from randomly arranged cell populations. This phenomenon has been studied often in the retina, due to its relatively simple layered organisation. In this review, I highlight the principal mechanisms that are thought to be involved, and how mathematical modelling has helped to further our understanding of the role of these processes upon mosaic formation. Three developmental mechanisms are studied in detail, namely, lateral migration, cell fate and cell death. As a case study, I then consider which mechanisms might be involved in the formation of retinal ganglion cell mosaics.

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PubMed2005

LL5beta: a regulator of postsynaptic differentiation identified in a screen for synaptically enriched transcripts at the neuromuscular junction.

In both neurons and muscle fibers, specific mRNAs are concentrated beneath and locally translated at synaptic sites. At the skeletal neuromuscular junction, all synaptic RNAs identified to date encode synaptic components. Using microarrays, we compared RNAs in synapse-rich and -free regions of muscles, thereby identifying transcripts that are enriched near synapses and that encode soluble membrane and nuclear proteins. One gene product, LL5beta, binds to both phosphoinositides and a cytoskeletal protein, filamin, one form of which is concentrated at synaptic sites. LL5beta is itself associated with the cytoplasmic face of the postsynaptic membrane; its highest levels border regions of highest acetylcholine receptor (AChR) density, which suggests a role in "corraling" AChRs. Consistent with this idea, perturbing LL5beta expression in myotubes inhibits AChR aggregation. Thus, a strategy designed to identify novel synaptic components led to identification of a protein required for assembly of the postsynaptic apparatus.

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PubMed2003

Mapping by waves. Patterned spontaneous activity regulates retinotopic map refinement.

A role for spontaneous spiking activity in shaping neuronal circuits has frequently been debated. Analyses of retinotopy in mutant mice with reduced correlated firing among neighboring retinal cells by Grubb et al. and McLaughlin et al. in this issue of Neuron indicate the importance of patterned spontaneous activity for retinotopic map refinement in subcortical visual targets.

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PubMed2003

Dopaminergic amacrine cells in the inner nuclear layer and ganglion cell layer comprise a single functional retinal mosaic.

Many types of retinal neuron are distributed in an orderly manner across the surface of the retina. Indeed, the existence of such regularity amongst a population of neurons, termed a retinal mosaic, may be a defining feature of functionally independent types of retinal neuron. We have examined the spatial distribution of dopaminergic amacrine cells in the ferret retina both in the inner nuclear layer (INL) and in the ganglion cell layer (GCL) to determine whether the cells in each layer form an independent retinal mosaic as evidence of whether they should be considered as two separate types. Ferret retinas contain approximately 1,900 dopaminergic amacrine cells, of which 27% are located in the GCL, and the rest in the INL. Based on analysis of their Voronoi domains as well as autocorrelation analysis and tests for complete spatial randomness, we found that the distribution of INL cells was statistically regular, while that of the GCL cells was not. However, by using cross-correlation analysis, these two groups of cells were found to be spatially dependent: an exclusion zone was detected in the cross-correlogram of roughly the same size as that found in the autocorrelograms of both INL and GCL cells. Such a pattern would be expected if dopaminergic amacrine cells in the INL and GCL were members of a single regular population differing only in their somatic depth. By using computer simulations, we tested this hypothesis directly, confirming that a random assignment of 27% from the total population produces cross-correlograms that are indistinguishable from those of the biological mosaics. We conclude, therefore, that the cells in the two layers form a single functional population; those in the GCL appear to be misplaced. Somatic positioning with respect to depth within the retina is not, by itself, a reliable guide for functional classification.

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PubMed2003

Developmental modulation of retinal wave dynamics: shedding light on the GABA saga.

Embryonic spontaneous activity, in the form of propagating waves, is crucial for refining visual connections. To study what aspects of this correlated activity are instructive, we must first understand how their dynamics change with development and what factors trigger their disappearance after birth. Here we report that in the turtle retina, GABA, rather than glutamate and acetylcholine, influences developmental changes in wave dynamics. Using calcium imaging of the ganglion cell layer, we report how waves switch from fast and broad, when they emerge, to slow and narrow a few days before hatching, coinciding with the emergence of excitatory GABA(A) receptor-mediated activity. Around hatching, waves gradually become stationary patches, whereas GABA(A) shifts from excitatory to inhibitory, coinciding with the upregulation of the cotransporter KCC2, suggesting that changes in intracellular chloride underlie the shift. Dark-rearing from hatching causes correlated spontaneous activity to persist, whereas GABA(A) responses remain excitatory, and KCC2 expression is weaker. We conclude that GABA plays an important regulatory role during the maturation of retinal neural activity. Using a simple and elegant mechanism, namely the switch from excitatory to inhibitory, GABA(A) receptor-mediated activity is necessary and sufficient to cause retinal waves to stop propagating, ultimately leading to the disappearance of correlated spontaneous activity. Moreover, our results suggest that visual experience modulates the GABAergic switch.

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PubMed2003

Determinants of the exclusion zone in dopaminergic amacrine cell mosaics.

A fundamental organizing feature of the retina is the presence of regularly spaced distributions of neurons, yet we have little knowledge of how this patterning emerges during development. Among these retinal mosaics, the spatial organization of the dopaminergic amacrine cells is unique: using nearest-neighbor and Vornoi domain analysis, we found that the dopaminergic amacrine cells were neither randomly distributed, nor did they achieve the regularity documented for other retinal cell types. Autocorrelation analysis revealed the presence of an exclusion zone surrounding individual dopaminergic amacrine cells and modeling studies confirmed this organization, as the mosaic could be simulated by a minimal distance spacing rule defined by a broad set of parameters. Experimental studies determined the relative contributions of tangential dispersion, fate determination, and cell death in the establishment of this exclusion zone. Clonal boundary analysis and simulations of proximity-driven movement discount tangential dispersion, while data from bcl-2 overexpressing mice rule out feedback-inhibitory fate-deterministic accounts. Cell death, by contrast, appears to eliminate dopaminergic amacrine cells that are within close proximity, thereby establishing the exclusion zone surrounding individual cells and in turn creating their mosaic regularity.

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PubMed2003

Developmental loss of synchronous spontaneous activity in the mouse retina is independent of visual experience.

In the immature retina, correlated spontaneous activity in the form of propagating waves is thought to be necessary for the refinement of connections between the retina and its targets. The continued presence of this activity in the mature retina would interfere with the transmission of information about the visual scene. The mechanisms responsible for the disappearance of retinal waves are not well understood, but one hypothesis is that visual experience is important. To test this hypothesis, we monitored the developmental changes in spontaneous retinal activity of both normal mice and mice reared in the dark. Using multi-electrode array recordings, we found that retinal waves in normally reared mice are present at postnatal day (P) 9 and begin to break down shortly after eye opening, around P15. By P21, waves have disappeared, and synchronous firing is comparable with that observed in the adult (6 weeks). In mice raised in the dark, we found a similar time course for the disappearance of waves. However, at P15, dark-reared retinas occasionally showed abnormally long periods of relative inactivity, not seen in controls. Apart from this quiescence, we found no striking differences between the patterns of spontaneous retinal activity from normal and dark-reared mice. We therefore suggest that visual experience is not required for the loss of synchronous spontaneous activity.

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PubMed2002

Segregation of ON and OFF retinogeniculate connectivity directed by patterned spontaneous activity.

In many parts of the developing nervous system, the early patterns of connectivity are refined by processes that require neuronal activity. These processes are thought to involve Hebbian mechanisms that lead to strengthening and maintenance of inputs that display correlated pre- and postsynaptic activity and elimination of inputs that fire asynchronously. Here we investigated the role of patterned spontaneous retinal activity and Hebbian synaptic mechanisms on segregation of ON and OFF retinal afferents in the dorsal lateral geniculate nucleus (dLGN) of the developing ferret visual system. We recorded extracellularly the spontaneous spike activity of neighboring pairs of ganglion cells and found that OFF cells have significantly higher mean firing rates than ON cells. Spiking is best correlated between cells of the same sign (ON, ON; OFF, OFF) compared with cells of opposite sign (ON, OFF). We then constructed a simple Hebbian model of retinogeniculate synaptic development based on a correlational framework. Using our recorded activity patterns, together with previous calcium-imaging data, we show that endogenous retinal activity, coupled with Hebbian mechanisms of synaptic development, can drive the segregation of ON and OFF retinal inputs to the dLGN. Segregation occurs robustly when heterosynaptic competition is present within time windows of 50-500 ms. In addition, our results suggest that the initial patterns of connectivity (biases in convergence of inputs) and the strength of inhibition in the network each play a crucial role in determining whether ON or OFF inputs dominate at maturity.

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PubMed2002

Influence of cell fate mechanisms upon retinal mosaic formation: a modelling study.

Many types of retinal neurone are arranged in a spatially regular manner so that the visual scene is uniformly sampled. Several mechanisms are thought to be involved in the development of regular cellular positioning. One early-acting mechanism is the lateral inhibition of neighbouring cells from acquiring the same fate, mediated by Delta-Notch signalling. We have used computer modelling to test whether lateral inhibition might transform an initial population of undifferentiated cells into more regular populations of two types of differentiated cells. Initial undifferentiated cells were positioned randomly, subject only to a minimal distance constraint. Each undifferentiated cell then acquired either primary or secondary fate using one of several lateral inhibition mechanisms. Mosaic regularity was assessed using the regularity index and the packing factor. We found that for irregular undifferentiated mosaics, the arrangement of resulting primary (but not secondary) fate cells was more regular than in the initial undifferentiated population. However, for regular undifferentiated mosaics, no further increases in the regularity of the primary fate mosaics were observed. We have used this model to test the specific hypothesis that on- and off-centre retinal ganglion cells emerge from an initial, irregular undifferentiated population of ganglion cells. Lateral inhibition can subdivide an initially irregular population into two types of cell that are mildly regular. However, lateral inhibition alone is insufficient to produce mosaics of the same regularity as observed experimentally. Likewise, and in contrast to earlier reports, cell death alone is insufficient to match the regularity of experimental mosaics. We conclude that lateral inhibition can transform irregular distributions into regular mosaics, upon which subsequent processes (such as lateral cell movement or cell death) can further refine mosaic regularity.

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PubMedDate not supplied

Homotypic constraints dominate positioning of on- and off-center beta retinal ganglion cells.

Beta retinal ganglion cells (RGCs) of the cat are classified as either on-center or off-center, according to their response to light. The cell bodies of these on- and off-center RGCs are spatially distributed into regular patterns, known as retinal mosaics. In this paper, we investigate the nature of spatial dependencies between the positioning of on- and off-center RGCs by analysing maps of RGCs and simulating these patterns. We introduce principled approaches to parameter estimation, along with likelihood-based techniques to evaluate different hypotheses. Spatial constraints between cells within-type and between-type are assumed to be controlled by two univariate interaction functions and one bivariate interaction function. By making different assumptions on the shape of the bivariate interaction function, we can compare the hypothesis of statistical independence against the alternative hypothesis of functional independence, where interactions between type are limited to preventing somal overlap. Our findings suggest that the mosaics of on- and off-center beta RGCs are likely to be generated assuming functional independence between the two types. By contrast, allowing a more general form of bivariate interaction function did not improve the likelihood of generating the observed maps. On- and off-center beta RGCs are therefore likely to be positioned subject only to homotypic constraints and the physical constraint that no two somas of opposite type can occupy the same position.

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