Tokuoka, S. M., Saiardi, A., Nurrish, S. J. (2008). The Mood Stabilizer Valproate Inhibits both Inositol- and Diacylglycerol-signaling Pathways in Caenorhabditis elegans. The EMBO Journal19(5), 2241-2250
Synapses are essential for information processing in the brain. A key feature of synaptic transmission is its plasticity: alterations to synaptic activity can occur at the level of individual synapses or can involve co-ordinated changes to billions of synapses in response to external regulators. Examples of factors that act throughout the brain are the neuromodulators serotonin and dopamine, which are believed to play a role in regulating global behavioural states such as mood. In humans, serotonin has been implicated in several aspects of mood and behaviour, including depression, eating disorders, alcohol consumption, and aggression. Dopamine has been implicated in movement control, motivation and reward, Parkinson’s disease, and schizophrenia. Both serotonin and dopamine signalling are targets for drugs: cocaine and amphetamines target dopamine pathways, and MDMA (esctasy) targets serotonin pathways. Although many of the molecular components that underlie synaptic transmission have been characterized, less is known about how they are regulated by neuromodulators and their associated intracellular signalling pathways. Our goal is to understand the signalling pathways that lead from neuromodulator receptors on the neuronal cell surface to changes in synaptic activity.
The Nurrish lab has used a genetic approach to understand how the neuromodulator serotonin can alter activity at a model synapse– the C.elegans neuromuscular junction (NMJ). Genetic screens for mutants defective in their response to serotonin defined two competing G protein pathways that facilitate or inhibit the release of acetylcholine (ACh) at the NMJ and thus alter the rate of locomotion. Our work, along with that of others, has identified a network of signalling pathways that converge to regulate the release of small and dense core synaptic vesicles (Figure 1). Work in mice knockouts has demonstrated that much of the pathway identified in C.elegans also controls mammalian neurotransmitter release. The lab is currently focuses around two main projects –
In particular we have demonstrated the important role of the RhoA GTPases in the control of adult neuronal activity. Rho GTPases play an important role in mammalian synaptic function and adult mice lacking Rho regulators and effectors such as PAK, WAVE-1, or LIMK-1 have learning and memory defects, while mutations in human genes encoding Rho GTPase regulators (ARHGEF6, OPHN1, FGD1, OCRL1, MEGAP) or effectors (LIMK-1, PAK3) are associated with human mental retardation. Currently Rho GTPases are thought to cause mental retardation due to developmental and structural defects in neurons. However, our work and that of others suggests that some Rho GTPase associated mental retardation is due to ongoing problems in neuronal activity and could be alleviated by targeting neuronal Rho signalling pathways with drugs. Indeed any drugs that target neuronal signalling proteins identified in our screens could have beneficial effects on patients suffering from defects in neuronal signalling, including patients with mental retardation, Alzheimer’s, and autism. Our screen for RHO-1 suppressors has identified 20 genes, three of which have been identified: unc-80 which has led to the discovery of the NALCN ion channel complex and a PI4P5 Kinase; dat-1 the dopamine reuptake transporter whose human ortholog is the target of drugs such as cocaine; and unc-31 the ortholog of CAPS (Calcium Activator of Protein Secrection), which is required for release of neuropeptides and other cargoes from Dense Core Vesicles (DCV). All three genes provide new insights into how Rho GTPases regulate neuronal activity and their role in RHO-1 signalling is being investigated both in C.elegans and in mammalian neurons through a collaboration with the Cutler lab within the MRC LMCB. Our results convince us that identifying the remaining RHO-1 suppressor mutants will be informative and we aim to identify many, if not all, the remaining 17 RHO-1 suppressors and these will form projects for future students and post-docs. Many genes first identified as having a role in C.elegans neurons have subsequently been shown to be important for mammalian brain function, e.g. UNC-13 and UNC-18, demonstrating the efficacy of C.elegans as a model for the mammalian brain. For this reason we believe the genes and their signalling pathways that we will identify will have important impacts on our understanding of both normal and abnormal mammalian brain function.
A second project aims to investigate the role of neuroligin-related carboxylesterases in synapse function. Neuroligins have been implicated in the correct functioning of mammalian synapses and mutations in human neuroligins have been implicated in autism. We have identified the nz90 mutation, which causes a decrease in both release of acetylcholine (ACh) and numbers of cholinergic synapses. nz90 has been mapped to a group of carboxylases that are related to neuroligins and transgenes carrying two of these carboxylases rescues the neurotransmitter release defect. Our studies of the nz90 mutation suggest that a family of neuroligin related genes is required for synapse function. Study of the carboxylesterase genes in C.elegans and their orthologs in mammals could reveal new features of synaptic function and offer new insights into autism and other neurodegenerative and psychiatric diseases