Why use C. elegans to study the synapse ?
In the mammalian nervous system a single neuron receives thousands of inputs from tens of neuronal subtypes. Opposite each neurotransmitter release site, receptors for this specific neurotransmitter are clustered within a specialized postsynaptic domain that ensures fast neurotransmission and coupling to the signal transduction machinery. Changing the receptor composition of the post-synaptic domain will affect the strength of synapse transmission, a plasticity mechanism presumably involved in learning and memory. In addition, innate or acquired perturbations of the post-synaptic domain will affect neuronal networks and cause nervous system dysfunctions. Understanding the mechanisms participating in these different processes will contribute to better understanding of brain function and diseases.
However, a challenging feature of the nervous system is complexity : the human brain contains 100 billion neurons and probably one thousand times more synapses. To circumvent this problem, we use the worm Caenorhabditis elegans as a model system. This 1 mm long non-parasitic soil nematode was introduced as a model organism by Sydney Brenner in the late 1960s. It comprises less than 1,000 cells, reproduces in about three days at room temperature on E. coli lawns and can be easily manipulated. Powerful genetic tools have enabled the analysis of various biological processes. For example, the genes that control programmed cell death were first identified in C. elegans and subsequently shown to be conserved throughout the entire animal kingdom. This finding had important implications for understanding normal development as well as human diseases such as cancer, autoimmune and neurodegenerative diseases. This discovery was acknowledged by a Nobel prize given to Sydney Brenner, John Sulston and Bob Horvitz in 2002. More recently, the inactivation of gene expression through double-stranded RNA (RNAi or RNA interference) that was discovered in C. elegans opened a new area of investigation and enabled the development of new tools for basic research and future disease treatments.
C. elegans is particularly interesting for cellular and molecular neurobiology studies. The nervous system is simple and only contains 302 neurons and 7,000 synapses. Since development is reproducible among individuals, each neuron can be individually identified. Moreover, the entire connectivity of the nervous system has been reconstructed by John White and colleagues using serial electron micrographs. Completion of the C. elegans genome sequence in 1998 demonstrated that almost all gene families involved in neuron function in mammals are present in the worm. Genetic analysis of the C. elegans nervous system benefits from the ability to propagate mutant animals with severe impairments of neural function. Therefore, forward genetic screens are powerful tools to identify genes required for specific neuronal functions and behaviors. Moreover, studies of mutant phenotypes can identify the function of a protein in the nervous system. Using a combination of genetic, biochemical and morphological tools, we are analyzing various aspects of the synapse biology, with a specific interest in the formation and regulation of post-synaptic receptor fields in nicotinic neurotransmission.