Molecular mechanisms underlying neural circuit 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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