Central to the function of the nervous system is its dynamic ability to undergo changes, for instance in the physiological properties of its constituent neurons, the synaptic connections between them, and the characteristics of individual synapses. The hypothesis that neuronal activity can lead to such plasticity, first proposed by the neurophysiologist Donald Hebb in 1949, is fundamental to brain science, and has been confirmed in many studies1. On page 165, Hart and Hobert2 describe an example of experience-dependent neural plasticity in the nematode worm Caenorhabditis elegans, a species in which this phenomenon has been little studied3.
It is important to demonstrate this already well-described and widely studied neural phenomenon in a nematode because C. elegans is not just any worm, but a powerful experimental model. Genetic studies in C. elegans have led to the discovery of several molecular components common to all nervous systems. Furthermore, a complete map of neural connectivity in the nematode nervous system has been available for more than 30 years4,5 — such a connectome is not yet available for any other animal.
Assembly of the C. elegans connectome was made possible not only by the worm’s tiny size (1 millimetre long), but also because its cells are constant in number and identity, and its synaptic connections are largely conserved between individuals. These properties, together with the fact that connectivity data were obtained from only a few individuals, have created the impression that the C. elegans nervous system is exceptional in having a rigid and constant structure. Intuition suggests that this cannot be the case — the worm’s nervous system is so complex that it must be based on dynamic mechanisms. But few examples of variability in C. elegans neurons have been described until now.
The C. elegans inhibitory neuron DVB makes different connections in the worm’s two sexes: males and hermaphrodites4,6. A single process extends towards the head of the worm in both sexes, and a male-specific outgrowth towards the tail leads to the formation of synaptic connections to a neuron and muscles that control the movement of the male’s spicules — a pair of hardened structures that insert into the vulva of the hermaphrodite during mating6 (Fig. 1). The formation of these new synapses, and the loss of some old ones, mean that spicule movement comes under the inhibitory control of DVB. This refinement improves the male’s mating efficiency7. Hart and Hobert now show that this male-specific outgrowth of DVB occurs between days 1 and 5 of adult life. The outgrowth produces a branching neuronal architecture that, unlike many neuronal circuits in C. elegans, varies between individuals.
Hart and Hobert used fluorescent ‘reporter’ proteins to visualize DVB outgrowth and synapse formation. Their analysis reveals that outgrowth does not occur if the male does not experience copulatory activity. The authors then mimicked natural behaviours by using sophisticated genetic techniques to activate or inhibit the signalling or movement of DVB’s target neuron and muscles, respectively. This shows that activity in DVB’s targets stimulates the neuron’s outgrowth.
What molecular pathways might mediate DVB outgrowth? Neural cell-adhesion proteins are expressed on cell surfaces in the nervous system. They have extracellular protein–protein interaction domains that can mediate communication between cells, and are thought to have a role in encoding and building the nervous system’s synaptic structure8. Two of the best-studied proteins in this class are neurexin and neuroligin, which can interact with one another and are involved in synapse formation and regulation9. As such, they were natural candidates for Hart and Hobert to test.
The authors examined the roles of these proteins by combining genetic deletion or overexpression of the proteins with stimulation or suppression of activity in the circuit. These analyses led to several findings. First, neurexin is expressed in DVB and is required for DVB outgrowth. Second, the activity of neurexin is inhibited by neuroligin, which is expressed in male sex circuits and muscles. Third, neuroligin expression is suppressed by activity in the circuit, which explains why DVB outgrowth is activity dependent. Precisely how neuroligin inhibits DVB outgrowth, and whether the two proteins physically interact in this setting, remain to be determined.
Hart and Hobert’s work brings together three areas of study in neuroscience: outgrowth, branching and target selection in plastic neurons; control of these processes through neuronal activity; and the function of neural cell-adhesion proteins. The value of the study therefore lies not only in the discovery of a new phenomenon, but also in the framework it provides for making more discoveries.
Analysis of C. elegans mutants will make it possible to identify additional molecules that affect DVB outgrowth, such as the binding partner of neurexin that stimulates outgrowth. The intracellular mechanisms that drive DVB outgrowth, and how they are controlled by interactions between neurexin and its binding partner, can then be analysed. Other questions for study include how DVB knows where to send processes, how its axonal extensions recognize appropriate synaptic targets, and precisely how circuit activity controls neuroligin expression.
Finally, Hart and Hobert found that these events occur only in males. The authors attempted to stimulate DVB outgrowth in hermaphrodites, but their results suggest that neither circuit activity nor the neurexin–neuroligin pathway are by themselves sufficient to do this. Other work10 in C. elegans suggests that it is the complement of sex chromosomes (two X chromosomes in the hermaphrodite and only one in the male) in the cells of the circuit that ultimately makes them respond to sex-neutral pathways in sex-appropriate ways.
Genetic studies9 have implicated mutations in neural cell-adhesion genes, including neurexin and neuroligin, as the bases of psychiatric disorders, partly because of the roles of these genes in neural plasticity. Progress in unravelling details of the molecular pathways underlying their activity could therefore have profound implications for understanding not only learning and memory, but also mental disorders and their sex-specific expression.
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