The origin of spontaneous activity in developing networks of the vertebrate nervous system
Introduction
Research over the past 10 years has established that spontaneous activity is a characteristic feature of developing neuronal networks. This work has been performed in various parts of the nervous system, in a wide variety of species and at several different developmental stages. Despite the diversity of these investigations, several general principles are beginning to emerge concerning the genesis of spontaneous activity by developing networks. In this review, I will discuss these principles in the context of the activity produced by developing synaptic networks in the vertebrate nervous system. An important distinction — and one that is often not made — is between the activity generated before and after the formation of chemical synaptic networks; many publications confuse the two phenomena, which are generated by different mechanisms and probably subserve quite different developmental functions.
The earliest studies of activity in the developing nervous system involved observations of embryonic motility. Such observations had been made for at least 300 years, and many of them were collected and described by Preyer in his monograph published in 1885 (and reprinted in English in 1937 [1]). In this monograph, he describes embryonic movements in an extraordinary diversity of species, including invertebrates, fishes, amphibians, reptiles, birds and mammals. Modern research on embryonic motility was inaugurated by Hamburger and his colleagues 2, 3, who studied the development of embryonic movements in the chick, supplementing observation with electromyography and electrophysiology. These early studies identified two features of embryonic motility that have been found to characterize spontaneous activity in all parts of the developing nervous system examined so far. First, the activity is restricted to a particular period of development and, secondly, it is organized into bouts or episodes separated by periods of quiescence. To understand the genesis of this activity, several conditions need to be fulfilled. First, it is essential to identify which neuron classes generate the activity and which members of the network are output elements. Second, it is necessary to establish what initiates and terminates the activity. Finally, the factors determining the organization of the activity in space and time must be identified.
I will describe progress in understanding these mechanisms in three parts of the nervous system that have been studied the most extensively: the spinal cord, the hippocampus and the retina. Spontaneous activity has been recorded from several other regions, but its mechanisms have not been addressed systematically 4, 5, 6, 7, 8, 9. The activity produced by cultured cortical neurons has also been studied and bears many similarities to developing network activity, but will not be covered here as it has recently been discussed elsewhere [10].
Section snippets
Distinct types of spontaneous activity are produced before and after the development of chemical synaptic networks
Activity produced by the early nervous system, before the formation of synaptic networks, comprises calcium transients that are coordinated in groups of cells coupled by gap junctions. This type of activity has been observed in the early mammalian cortex 11, 12, the avian retina [13] and the amphibian neural tube (for a review, see [14]). Cells of the amphibian neural tube express two types of calcium transient that have been denoted ‘spikes and waves’ [14]. Spikes rise rapidly and decay over
Mechanisms of network-driven spontaneous activity
Once chemical synaptic networks form, a new type of activity emerges that I will refer to as network-driven activity. It is abolished by tetrodoxin (TTX) or by antagonists of chemical synaptic transmission, and it involves the synchronous activation of many, if not all, members of a particular network through their synaptic interactions. In what follows, I will describe the activity produced in several regions of the nervous system and discuss what is known about the mechanism of its genesis. I
Common mechanisms may operate in the production of spontaneous activity by diverse, developing networks
One striking conclusion to emerge from the work I have discussed above is that common mechanisms may operate in the activation of networks as diverse as the retina and spinal cord. In many systems, spontaneous activity appears to be generated by network interactions — in particular, positive feedback excitation in a recurrently connected, excitatory network. The precise mechanisms for termination of this activity, and the factors that control the duration of quiescent periods, are not fully
Conclusions
Accumulating evidence suggests that the high excitability of developing networks coupled with some form of transient, activity-dependent network depression underlies the genesis of spontaneous activity by synaptically coupled networks. It also seems likely that the mechanisms responsible for spontaneous activity will be intimately connected with those regulating synaptic efficacy during development. A major challenge for the future will be to disentangle these two aspects of network development
Acknowledgements
Particular thanks to Rachel Wong and Michael Weliky for discussing published and unpublished work. Special thanks to Evelyne Sernagor for providing the unpublished data illustrated in Figure 3d. Thanks are also due to Uri Cohen, Patrick Whelan, Joel Tabak, Nikolai Chub and Agnes Bonnot for their comments on earlier versions of the manuscript.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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