A. van Ooyen

The role of calcium signaling in early axonal and dendritic morphogenesis of rat cerebral cortex neurons under non-stimulated growth conditions.

The effects of depolarizing stimuli on neurite outgrowth have been shown to depend on an influx of extracellular calcium. However, the role of calcium under non-stimulated growth conditions is less well established. Here we investigated the contribution of calcium signaling to early neuronal morphogenesis of rat cerebral cortex neurons at three levels by blocking L-type voltage sensitive calcium channels, by depleting intracellular calcium or by blocking myosin light chain kinase. Detailed quantitative morphological analysis of neurons treated for 1 day revealed that depletion of intracellular calcium strongly decreased the density of filopodia, arrested axonal outgrowth and strongly decreased dendritic branching. Preventing calcium influx through L-type voltage sensitive calcium channels and blocking of myosin light chain kinase activity selectively decreased dendritic branching. Our observations support an essential role for basal intracellular calcium levels in axonal elongation. Furthermore, under non-stimulated conditions calcium entry through L-type voltage sensitive calcium channels and myosin light chain kinase play an important role in dendritic branching.

Activity-dependent neurite outgrowth and neural network development

Publisher Summary From the studies on activity-dependent neurite outgrowth, the realization is growing that electrical activity and neurotransmitters are not only involved in information coding but also play an important role in shaping neuronal form and in defining the structure of the networks in which they operate. Using simulation models, this chapter explores the possible implications of activity-dependent outgrowth and locally interacting excitatory and inhibitory cells for neuronal morphology and network development. In this study, several interesting properties arise as the result of interactions among outgrowth, excitation and inhibition: (1) a transient overproduction during development with respect to synapse number or connectivity, both in purely excitatory and in mixed networks, (2) the neuritic fields of inhibitory and excitatory cells become differentiated, whereby those of inhibitory cells tend to become smaller, (3)the distribution of inhibitory cells becomes important in determining the ultimate level of inhibition, (4) inhibitory cells, by inducing outgrowth, can help to selectively connect sub-networks, (5) pruning of connections can no longer take place if the network has grown without proper electrical activity for longer than a certain time, and (6) excitatory cell death will be accompanied by an increased neuritic field of surviving neurons (compensatory sprouting).

Network connectivity changes through activity-dependent neurite outgrowth

There is experimental evidence that neuronal electrical activity directly influences neurite outgrowth during the development of the nervous system. Using model studies, Van Ooyen and Van Pelt extensively investigated the effect of this phenomenon upon network development and architecture. Their studies are based on the experimental observations that there is an optimal range of electrical activity at which neurite outgrowth takes place. In their model, neurite growth occurs if the activity level of the neuron is below a certain threshold, otherwise the neurite retracts. We extend their results to include a more complete description of the relationship between electrical activity and neurite outgrowth. This takes into account the experimental observation that outgrowth ceases not only when neuronal activity is too high, but also when it is below a certain threshold. The modified model displays a wider range of behaviours during network development. In some cases, for example, growth is only transient and is followed by a total loss of connections in the network. As a consequence of the larger spectrum of possible behaviours, the mechanisms for control of network formation, by the networks internal dynamics as well as by external inputs, are also increased.

Implications of Activity-Dependent Neurite Outgrowth for Developing Neural Networks

The presence of only two basic neuronal properties — a firing threshold and activitydependent neurite outgrowth — is sufficient to cause a transient overproduction of connections in developing neural networks. This overproduction is enhanced by inhibition. Solely as the result of activity-dependent outgrowth and local cell interactions, the neuritic field of an inhibitory cell becomes smaller than that of an excitatory cell. Furthermore, a specific distribution of cell sizes is generated in the area surrounding an inhibitory cell.

Phase Transitions, Hysteresis and Overshoot in Developing Neural Networks

We show that the presence of only two basic neuronal properties - a firing threshold and activity dependent outgrowth - is sufficient to generate overshoot phenomena in developing neural networks.

Complex Patterns of Oscillations in a Neural Network Model with Activity-Dependent Outgrowth

Many processes that play a role in shaping the structure of the nervous system are modulated by electrical activity. For example, electrical activity can affect neurite outgrowth: high levels of activity, resulting in high intracellular calcium concentrations, cause neurites to retract, whereas low levels of activity, and consequently low calcium concentrations, allow further outgrowth [1]. As a result of this and other activity-dependent processes, a reciprocal influence exits between the formation of connectivity (”slow dynamics”) and activity (”fast dynamics”). We have made a start at unravelling the implications of activitydependent neurite outgrowth [2, 3], and have been able to show that several interesting properties arise as the result of interactions among outgrowth, excitation and inhibition: (i) a transient overproduction (’overshoot’) during development with respect to connectivity; (ii) the neuritic fields of inhibitory cells tend to become smaller than those of excitatory cells; (iii) the spatial distribution of inhibitory cells becomes important in determining the level of inhibition; (iv) pruning of connections can no longer take place if the network has grown without activity for longer than a certain time (’critical period’). The results show many similarities with findings in cultures of dissociated cells.

Long-lasting transients of activation in neural networks

Abstract The question has been investigated whether long-lasting transients of activation (i.e. slow waves), observed to occur in the intact cerebral cortex (EEG ‘delta’ waves and ‘K’ complexes) as well as an isolated tissue cultured in vitro, can also emerge in a simplified neural network model of interconnected excitatory and inhibitory cells. It is shown that slow waves can indeed occur even if the cells in the network do not have explicitly built-in slow processes. The mechanism underlying the termination of transient activity depends crucially upon the presence of a refractory period and random activity, rather than upon inhibitory suppression. A wide range of characteristic unit firing patterns is associated with transient population activities, even though all the cells in the network model have identical response properties.

Effect of Low-Frequency Stimulation on Spontaneous Firing in Cultured Neuronal Networks

Cultured neuronal networks from dissociated rat cortical tissue show spontaneous firing activity from about the end of the first week in vitro. Multielectrode recordings have shown slow developmental changes in the firing activity at the individual electrode sites. Here we report that a short period of low-frequency electrical stimulation is able to induce lasting changes in the spontaneous firing activity, significantly larger than developmental changes over similar periods of time.