C. elegans Neural Development and Behavior

The nervous system of the nematode Caenorhabditis elegans is remarkably simple, yet it contains a broad variety of nerve cell types and many synaptic interconnections. For example, whereas a mammalian brain contains on the order of 1012 nerve cells and probably 1015 to 1016 synapses, the entire C. elegans nervous system contains 302 neurons and about 5000 chemical synapses, 2000 neuromuscular junctions, and 600 gap junctions. The 302 neurons are of 118 distinct classes, as defined by morphology, neurochemistry, and synaptic connectivity. C. elegans is the only animal for which the complete wiring diagram of the nervous system has been described. This uniquely high-resolution description of the C. elegans nervous system has allowed researchers at the McGovern Institute to analyze how a nervous system forms and how it functions to drive behavior.

To identify and analyze genes important to the nervous system, McGovern Institute researchers use methods of genetics, cell biology, molecular biology, biochemistry, and electrophysiology. They have identified and characterized many genes responsible for specific aspects of nervous system development, including the control of neuroblast cell division, the determination of neuronal cell fate, the choice between survival and programmed cell death (apoptosis), axonal outgrowth, and neurotransmitter expression. A major focus of their efforts is how the nervous system controls behavior. They use laser microsurgery, pharmacology, and mutations to identify which neurons control specific behaviors and to define complete neural systems responsible for specific behaviors. For example, they have analyzed how the environment and experience modulate the locomotory rate of C. elegans and have discovered that the animal's serotonergic nervous system plays a central role in its response to its experience. These studies have led to the identification and analysis of a novel ionotropic serotonin receptor (a serotonin-gated chloride channel) and a serotonin-reuptake transporter similar to the target of human antidepressants (e.g., Prozac). Genes that control a two-pore potassium channel complex involved in muscle contraction have also been identified.

McGovern Institute researchers are studying C. elegans models of amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) and other human genetic neurologic and/or aging disorders, including lissencephaly, mucolipidosis type IV and a progeroid variant of Ehlers-Danlos syndrome. In addition, in collaboration with others, McGovern Institute researchers showed that one gene responsible for the inherited form of ALS encodes the enzyme Cu/Zn superoxide dismutase (SOD), which catalyzes the conversion of the free radical superoxide to hydrogen peroxide. This finding supports a role for free radicals in neurodegenerative disease.