For many years, a major challenge for neuroscientists has been the identification of the proteins that are responsible for communication at synapses. Now, using a large-scale RNA interference (RNAi) screen in Caenorhabditis elegans, Sieburth and colleagues have discovered more than 100 genes that are important for synaptic communication. This study was made possible through the work of Wang and colleagues — published in an accompanying paper in Nature — who developed the innovative technique that was used to screen for these genes.

C. elegans neurons are normally insensitive to RNAi screens. However, Wang and colleagues made the unexpected discovery that genes in the C. elegans homologue of the mammalian retinoblastoma pathway negatively regulate RNAi. They showed that mutations to several components of this pathway enhance the effectiveness of RNAi, probably because neurons and other mature cells revert to immature germline cells, which have a heightened sensitivity to RNAi.

Sieburth and colleagues used these mutant forms of C. elegans to systematically search for genes that are implicated in neurotransmission at the neuromuscular junction by screening for a reduction in acetylcholine secretion following RNAi. In total, they identified 185 genes, 132 of which had not previously been implicated in synaptic communication.

These researchers went on to categorize the functional profiles of the genes by analysing the patterns of reduced acetylcholine secretion. This revealed that the candidate genes are involved in a range of functions during synaptic transmission, including exocytosis, endocytosis, formation of the active and peri-active zones, vesicle transport, and neuropeptide modulation at the synapse.

In support of a role for the protein products of these genes in synaptic communication, Sieburth and colleagues showed that many of the proteins are located in either presynaptic or postsynaptic regions. Furthermore, they examined mutants from classic genetic knockout studies and confirmed that a subset of the proteins is involved in synaptic functions.

This collaborative work has not only led to an important step forward in the search for genes that regulate synaptic communication, but has also demonstrated the promise of this powerful genetic tool for tackling some unresolved questions in neuroscience.