Molecular Genetics of Neurochemical Signaling Systems
Chemical neurotransmission is fundamental to nervous system function. The regulated release of neurotransmitters into synapses carries information between neurons. Neurochemicals also function to generate behavioral states by triggering widespread changes in the nervous system. The simple nervous system of the nematode C. elegans contains only 302 neurons but, strikingly, uses a repertoire of neurotransmitters and neuromodulators comparable to that used by vertebrate nervous systems. Behavioral genetic studies of C. elegans can therefore identify molecular components of neurochemical signaling pathways that function both in the context of synaptic signaling and in the generation of behavioral states. Our lab aims to use such studies to identify new genes that function in conserved neurochemical signaling pathways, specifically neuropeptide and biogenic amine signaling pathways. These genes might encode targets for novel therapeutics for psychiatric and neurological disorders.
A Sensorimotor Circuit that Regulates Reproductive Behavior
A simple neuromusculature drives the reproductive behavior of the C. elegans hermaphrodite, egg laying. We identified a neuropeptide signal that negatively regulates serotonergic motor neurons in this neuromusculature. Peptides encoded by the genes flp-10 and flp-17 activate the Go-coupled receptor EGL-6 to inhibit the serotonergic HSN motor neurons. The principal source of endogenous flp-17 peptides is a pair of sensory neurons, the BAG neurons, which have recently been shown to mediate behavioral responses to carbon dioxide (Hallem and Sternberg, 2008). Using molecular genetics and in vivo calcium imaging, we are isolating mutants defective in this inhibitory circuit and determining whether the affected genes function in the BAG sensory neurons i.e. in the detection of CO2 and regulated release of peptides, or in the HSN motor neurons i.e. in G protein signaling downstream of receptor activation.
Ionotropic Receptors for Biogenic Amines
Biogenic amines such as dopamine and serotonin are important neurotransmitters and neuromodulators in biology and medicine because of their connections to psychiatric conditions, including schizophrenia and major depression. C. elegans uses biogenic amines to modulate simple behaviors. In C. elegans, as in vertebrates, biogenic amines act through G protein coupled receptors. The C. elegans nervous system also expresses a serotonin-gated chloride channel: MOD-1. We have discovered three novel MOD-1-like receptors: a dopamine-gated chloride channel, a tyramine-gated chloride channel and a second serotonin-gated chloride channel. The discovery of these channels indicates that direct activation of membrane conductances is a general mechanism of action of biogenic amines, at least in the C. elegans nervous system. By identifying receptor-interacting proteins and isolating mutations that affect these ionotropic signaling pathways we hope to molecularly characterize the aminergic postsynapse in C. elegans.