491 Genetic approaches in flies and worms continue to dissect the intricate molecular machinery of chemical synapses. Investigations carried out in the last year provide important new insights into the development and modulation of the presynaptic active zones and postsynaptic receptor fields mediating synaptic function. Mutant screens have identified overlapping gene classes mediating synaptogenesis. The leucocyte common antigen-related receptor tyrosine phosphatase interacts with liprin in the formation of the active zone. Spectrins are essential for the spatial restriction of synaptic proteins to define active zones. Glutamate acts as a negative regulator of its cognate postsynaptic receptor to sculpt receptor field size. Finally, protein translation and degradation regulation emerge as possible key regulators of synaptic efficacy. Addresses *Department of Biological Sciences, Vanderbilt University, 4270 Medical Research Building III, 465 21st Avenue South, Nashville, Tennessee 37235-1634, USA; e-mail: kendal.s.broadie@vanderbilt.edu † Department of Biological Sciences, University of Illinois, 840 West Taylor Street, Chicago, Illinois 60607, USA Correspondence: Kendal S Broadie Current Opinion in Neurobiology 2002, 12:491–498 0959-4388/02/$ —see front matter © 2002 Elsevier Science Ltd. All rights reserved. Published online 4 September 2002 Abbreviations dFXR Drosophila Fragile X-related protein dlar Drosophila LAR receptor gene faf fat facets FMRP Fragile X mental retardation protein GABA γ-amino butyric acid GAD glutamic acid decarboxylase GFP green fluorescent protein GOT glutamate oxaloacetate transaminase GS glutamine synthetase hiw highwire JIP3 JNK-interacting protein 3 JNK c-Jun N-terminal kinase LAR leucocyte common antigen-related LQF liquid facets MAP1B microtubule-associated protein 1B NMJ neuromuscular junction PAR1 proteinase-activated receptor 1 RIM Rab3a-interacting molecule sad synapses of the amphid defective sam synapse abnormal morphology SV synaptic vesicle syd synapse defective Unc uncoordinated UPS ubiquitin proteasome system Introduction Drosophila melanogaster and Caenorhabditis elegans are the two forward genetic systems used to dissect the molecular mechanisms of synaptic function. Both animals invite systematic forward genetic screens to identify novel components of the synapse, and allow reverse genetic approaches to test hypothesized synaptic functions of known proteins. These genetic systems are complementary, as each has its own particular strengths and weaknesses. The Drosophila system, particularly the glutamatergic neuromuscular junction (NMJ), is best adapted to sophis- ticated cellular assays of synaptic mechanisms. The fly NMJ is accessible throughout its embryonic development and, in mature larvae, forms a large, elaborate architecture that lends itself to detailed analyses of synaptic morphology (Figure 1) [1]. Individual NMJ boutons are as large are 5 μm in diameter, allowing subcellular resolution within both presynaptic and postsynaptic compartments, precise assays of synaptic vesicle dynamics with lipophilic dyes and/or transgenic fluorescent fusion proteins, and Ca 2+ imaging studies (Figure 1). The Drosophila NMJ has proven to be particularly well suited to a wide range of electrophysiological assays, including loose-patch recording from single synaptic boutons and multiple forms of use-dependent functional plasticity [2]. The C. elegans system is more amenable to rapid genetic screens that identify synaptic mutants, and for making extensive mutant allelic series of any targeted gene. Because C. elegans are viable and self-fertile in the near complete absence of synaptic function, it is possible to isolate a wider range of mutants on the basis of adult behavioral defects, and to study these impaired mutants as adults. Comparable Drosophila mutants are embryonic- lethal and such genes can be studied in adults only via rare conditional mutations. Nevertheless, C. elegans adults are roughly the same size as Drosophila embryos, making cellular assays, even in adults, technically challenging (Figure 1). An enormous recent breakthrough has been the first successful synaptic recordings at the C. elegans NMJ [3,4], muscles innervated by both cholinergic and γ-amino butyric acid (GABA)ergic terminals (Figures 1 and 2). Using approaches first developed in the Drosophila embryo, it is now feasible to make whole-cell patch-clamp recordings from the muscle coupled to presynaptic stimulation and/or the application of exogenous signals (e.g. receptor agonists, hyperosmotic saline). Thus, in just the last few years, C. elegans studies have advanced to combine the enormous power of rapidly identifying synaptic mutants with detailed functional studies of these mutants at the level of the synapse. This review aims to highlight the advances in our understanding of synaptic mechanisms made using genetic approaches in Drosophila and C. elegans during (roughly) the last year. All of the studies discussed here have been done at the NMJ, a glutamatergic synapse in flies and a cholinergic/GABAergic synapse in worms. We consider Establishing and sculpting the synapse in Drosophila and C. elegans Kendal S Broadie* and Janet E Richmond †