Serotonin is an important neuromodulator involved in many physiological processes, such as mood, appetite, and aggression. Altered serotonin levels have been linked to several neurological disorders, such as major depressive disorder, panic disorder, and generalized anxiety disorder. The mechanism of serotonin signaling is not well understood, resulting in a continued demand for improved therapeutics. The therapeutics that do exist are not always effective and often cause off-target side effects. Understanding the mechanism of serotonin signaling is the first step to creating more effective treatments for patients. The nematode worm C. elegans is a powerful model for studying serotonin signaling. It has a short generation time and well-understood genetics, and its reproductive behavior, egg laying, is driven by serotonin. The egg-laying circuit is comprised of only three cell types, and egg laying is an easy-to-assay behavior. Animals carrying mutations that affect serotonin signaling become bloated with unlaid eggs, making them easily identifiable. One such mutation is egl-6(gf). egl-6 encodes a neuropeptide receptor that is expressed by the pair of serotonergic motor neurons, the HSNs, that drive egg laying. EGL-6 inhibits serotonin release from the HSNs, and animals with a gain-of- function mutation (egl-6(gf)) do not release enough serotonin, causing the animals to become bloated with unlaid eggs. To discover novel regulators of serotonin signaling, a screen for suppressors of egl-6(gf) was performed. The screen yielded a mutation in cca-1. This means that egl-6(gf) animals are bloated with unlaid eggs, but egl-6(gf) cca-1 mutant double mutants exhibit wild-type egg-laying behavior. cca-1 encodes a T-type calcium channel. T-type calcium channels regulate neuronal excitability, or how easily neurons respond to stimuli. In humans, mutations in T-type calcium channels have been linked to several pathological states including absence epilepsy. Because cca-1 mutation potently suppresses egl-6(gf), it was hypothesized that CCA-1 would be expressed by the HSNS alongside EGL-6. However, it is not.
The first aim of this proposal is to determine in what cells CCA-1 acts.
The second aim i s to understand how cca-1 mutation changes the functional connections of the cells in the serotonergic egg-laying circuit. The finding that a mutation in a T type calcium channel can profoundly affect a serotonin-driven behavior was novel and unexpected. The proposed studies will establish a link between serotoninergic circuits and T-type calcium channels. By identifying the cells that are affected by cca-1 mutation, determining how they are functionally coupled to serotonin neurons, and determining how mutation of a T-type channel alters that coupling, these studies will elucidate mechanisms required for the effects of serotonin on a neural circuit to regulate behavior. These studies will advance our understanding of how this neuromodulator system, which is targeted by many therapeutics, can be modulated and manipulated.
Serotonin is an important neuromodulator involved in many physiological processes, including mood, appetite, and aggression, and altered serotonin levels have been linked to several neurological disorders. T- type calcium channels play a role in regulating cellular excitability, and mutations in these channels have been associated with absence epilepsy and the tremor associated Parkinson's disease. My studies are establishing a link between serotonin and T-type calcium channels, and they will advance our understanding of how serotonin systems, which is targeted by many therapeutics, can be modulated and manipulated.
| Zang, Kara E; Ho, Elver; Ringstad, Niels (2017) Inhibitory peptidergic modulation of C. elegans serotonin neurons is gated by T-type calcium channels. Elife 6: |
