Molecular mechanisms underlying neural circuit formation

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The functions of the nervous system are mediated by neural circuits that are formed during development and modulated by experiences. Central to the assembly of neural circuits is the regulation of synaptic connectivity by synaptic molecules and neuronal activity. Extensive studies have focused on identifying molecules involved in synapse formation. Besides factors promoting synaptogenesis, several antisynaptogenic factors have been discovered. These factors act in concert to ensure the timing and specificity of circuit formation. Moreover, progress has been made in revealing how neuronal activity governs the balance of excitatory and inhibitory synapses. Intriguingly, several transcription factors, as well as activity-dependent transcription of BDNF through promoter IV, have been shown to selectively regulate cortical inhibitory circuits by promoting GABAergic synapse formation.

Introduction

How does an axon (or dendrite) choose among numerous available dendrites (or axons) to form a synapse that not only functions but also lasts for a long time? It is well known that mammalian synapses rarely form at their first encounter. Instead, long-lasting marriage of the presynaptic and postsynaptic partners is a consequence of a lengthy ‘dating’ process that involves a series of meetings, dancing, and touching. Only the right partners eventually wed. The cellular and molecular mechanisms underlying the formation of specific synaptic connections have long been a mystery. Regardless of its complexity, it is generally agreed that the dating of synaptic partners involves two sequential processes. First, the synaptic partners have to click with each other; the presynaptic axon and postsynaptic dendrites need to have the right ‘physical chemistry’. Second, after initial molecular interactions that ensure the parties have the right matches, an activity-dependent process kicks in. The synaptic partners engage in serious talks. However, the synaptic dating does not need to be one-to-one. In fact, there are often competitions. The relationship gets refined and strengthened if the presynaptic and postsynaptic partners talk (fire) in synchrony, whereas those who cannot speak harmoniously (fire asynchronously) are eliminated. Armed with knowledge cumulated over the past decade in related fields as well as advances in tools and technologies, recent studies have begun to reveal the secret of how stable and specific synaptic connections are formed. In this review, we will first discuss a set of new studies that reveal how early axon–dendritic interactions help to find synaptic partners in the right categories. We will then highlight recent progress in identifying synaptogenic and antisynaptogenic factors that strengthen the appropriate connections, as well as how neuronal activity controls the expression of genes that shape and coordinate the formation and stability of neuronal circuits.

Section snippets

Initial selection of synaptic partners  role of local filopodial Ca2+

Using two-photon time-lapse imaging of fluorescence-labeled presynaptic and postsynaptic partners, motion pictures have been made to describe the initial ‘dating’ process [1•, 2•]. Surprisingly, dendritic filopodia, the precursor of dendritic spines, seem to know which axonal targets are suitable for a long-term relationship after initial contacts. In slice cultures of hippocampus in which postsynaptic CA3 pyramidal cells were labeled by a red dye, Lohmann and Bonhoeffer observed that filopodia

Synaptogenic and antisynaptogenic factors

After initial contacts, further development of synaptic relationships depends largely on the right molecular chemistry. Neuroligins and neurexins are possibly the best-known trans-synaptic CAMs that connect presynaptic and postsynaptic cells [3]. Previous in vitro analyses demonstrated that neuroligins and neurexins could reciprocally instruct presynaptic and postsynaptic specializations, suggesting that these molecules function as bidirectional inducers for synaptogenesis [3]. Surprisingly,

Activity-regulated gene expression and coordinated development of glutamatergic and GABAergic synapses

While genetically prespecified molecular recognition mechanisms may be important in connecting specific synaptic partners, neural activity-regulated gene expression programs appear to play a key role in orchestrating the assembly of neural circuits, which contain synaptic connections among diverse types of neurons. Genome-wide gene expression analyses have revealed several hundreds of genes whose expressions are acutely regulated by membrane depolarization or neural transmitter release [23].

Conclusion

Contrary to previous belief, developing neurons exhibit preference to their future synaptic partners, at least grouped by large categories (GABAergic or glutamatergic), during early stages of synaptogenesis. It has become increasingly clear that the formation of appropriate synaptic networks involves both synaptogenic and antisynaptogenic factors, which control the specificity as well as timing of synaptogenesis. Cumulating evidence also suggests that neuronal activity orchestrates the

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to thank Hiroki Taniguchi for comments and Makiko Shinza-Kameda for the help in Illustration (Figure 1). This article is supported by a Grant-in-Aid to AN for Scientific Research B and for Scientific Research on Priority Areas  Molecular Brain Science  from the MEXT, and by the NICHD and NIMH intramural research programs to BL and KHW.

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