Title: Identifying intracellular signalling pathways that regulate neuronal activity
Funder: Medical Research Council

Abstract: Extracellular neuromodulators alter levels of neurotransmitter release at many, if not all, synapses. Examples include the monoamines serotonin and dopamine, which control global behavioural states of the brain. 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, Parkinsons disease, and schizophrenia. Both serotonin and dopamine signalling are targets for drugs: cocaine and amphetamines target dopamine pathways, and MDMA (ecstasy) targets serotonin pathways. Although many of the molecular components that underlie neurotransmitter release 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 cell surface to the control of neurotransmitter release.||Our research uses the model organism C.elegans, in particular the C.elegans neuromuscular junction (NMJ). We and others have shown that C.elegans uses both serotonin and dopamine to modulate NMJ activity using pathways conserved in human neurons. Many of the genes that regulate activity at the NMJ participate in a network of heterotrimeric G-protein signalling pathways controlling the release of synaptic vesicles and/or dense core vesicles (DCVs). At least four heterotrimeric G-proteins (G-alpha-q, G-alpha-12, G-alpha-o and G-alpha-s) act within the motorneurons to control the activity of the NMJ. The G-alpha-q, G-alpha-12, and G-alpha-o pathways converge to control production and destruction of the lipid bound 2nd messenger diacylglycerol (DAG) at sites of neurotransmitter release. DAG acts via at least two effectors, MUNC13 and PKC, to control the release of both neurotransmitters and neuropeptides from motorneurons. The G-alpha-s pathway converges with the other three heterotrimeric G-protein pathways downstream of DAG to regulate neuropeptide release. Released neurotransmitters and neuropeptides then act to control contraction of the bodywall muscles to control locomotion.||Current work focuses on a novel role for RhoA GTPases in the control of neuronal activity in adult neurons. Due to a requirement for RhoA in neuronal development the role of RhoA in adult neurons has been previously missed. Interestingly, many RhoA regulators and effectors have been implicated in human mental retardation and our work suggests this could be due to defects in neuronal activity rather than development. If true this makes it more likely that some forms of human mental retardation could be corrected in adults. RhoA increases neuronal activity in part by inhibiting the DAG kinase DGK-1. This leads to an increase in DAG and thus an increase in neurotransmitter release. However, we have also shown that other pathways exist downstream of RhoA to increase neuronal activity. A genetic screen for RhoA suppressors has identified at least 12 mutations and a combination of genetic mapping and whole genome sequencing is being used to clone these mutations. One mutation is in the nca-1 gene, a homolog of the human NALCN channel. We continue to work on how RhoA regulates the NALCN channel and the other suppressors.||The lipids and proteins involved in these networks are conserved between C.elegans and mammals. Thus, the C.elegans NMJ acts as a model synapse to understand how neuronal activity in the human brain is regulated.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE