|
|
RESEARCH INTERESTS
Neurobiology; synaptic structure, function and development
PUBLICATIONS
Description of Research Program
A current challenge in neuroscience is to bridge the gaps between genes, proteins, neurons, neural circuits, and behavior in a single animal model. The nematode Caenorhabditis elegans has unique features that facilitate this synthesis. Its nervous system includes exactly 302 neurons, and their pattern of synaptic connectivity is known. The neurons are organized in neural circuits that process information and control behavior. How are these circuits constructed? What molecules are required for circuit function? Recent developments in genetics, electrophysiology, and cell biology have made feasible a strategy to deconstruct the function of neural circuits and the control of behavior. In the past several years we have made major advances in understanding how specific signaling molecules contribute to synaptic function and the behavior of C. elegans. Below, I describe three areas of research in my laboratory.
I. Analysis of Glutamate Receptor Function in Caenorhabditis elegans
Glutamate is the major excitatory neurotransmitter in the brain and exerts its actions by binding to several classes of glutamate-activated receptors. Since dysfunction of glutamate-receptor-mediated signaling is implicated in various mental health and neurological disorders, there is intense interest in gaining a greater understanding of the molecules required for the assembly, localization and function of ionotropic glutamate receptors (iGluRs).
In my laboratory, we have demonstrated that AMPA (GLR-1, GLR-2) and NMDA (NMR-1) subtypes of glutamate receptors contribute to specific avoidance and foraging behaviors in C. elegans. How are the function of these receptors regulated and how are they localized to synapses? Using a genetic approach we have identified a new transmembrane protein, SOL-1 that co-localizes with GLR-1 and that is absolutely required for AMPA receptor function. More recently, we have found a second transmembrane protein that is required for glutamate-gated currents. These new discoveries will help provide a mechanistic understanding of how different classes of iGluRs are distributed to and maintained at specific synapses, how they participate in synaptic communication, and how they contribute to the behavior of C. elegans.
II. Analysis of neuromuscular development and function in C. elegans
Nicotinic (cholinergic) neurotransmission plays a critical role in the vertebrate nervous system, underlies nicotine addiction and nicotinic receptor dysfunction leads to neurological disorders. The C. elegans neuromuscular junction (NMJ) shares many characteristics with neuronal synapses, including multiple classes of post-synaptic currents. We have identified two genes required for the major excitatory current found at the C. elegans NMJ: acr-16, which encodes a nicotinic AChR subunit homologous to the vertebrate _7 subunit, and cam-1, which encodes a Ror receptor tyrosine kinase. CAM-1 is expressed at both sides of the synapse and has critical roles in the establishment of functional cholinergic synapses. Future studies will focus on identifying the molecular machinery that is required for the development and function of cholinergic synapses.
III. Studies of rhythmic behavior and Ca2+ oscillations in C. elegans
Rhythmic activities are ubiquitous biological phenomena and can be observed in cells, tissues and the behavior of most organisms. For example, heart and respiratory rate, intestinal peristalsis, circadian activity, and ovulation are all rhythmic behaviors and reflect the underlying activities of a diverse array of regulatory pathways. Pharyngeal pumping, defecation cycle and gonadal sheath cell contractions are three well-characterized rhythmic behaviors in the nematode C. elegans. The periodicities of the rhythms range from subsecond (pharynx), to seconds (gonadal sheath), to minutes (defecation). However, the molecular mechanisms underlying these rhythmic behaviors are not well understood. We have found that the C. elegans Rho/Rac family guanine nucleotide exchange factor, VAV-1, has a crucial role in all three behaviors. The VAV-1 signaling pathway appears to controls rhythmic behaviors by dynamically regulating the concentration of intracellular Ca2+ . Future studies will focus on identifying other gene products that contribute to the VAV signaling pathway and the regulation and generation of rhythmic behaviors.
Francis, M.M., Evans, S.P., Jensen, M., Madsen, D.M., Mancusco, J., Norman, K., and Maricq, A. V. (2005) The Ror Receptor Tyrosine Kinase CAM-1 is Required for ACR-16 Mediated Synaptic Transmission at the C. elegans Neuromuscular Junction. Neuron, 46: 581-594.
de Bono, M., and Maricq, A.V. (2005) Neuronal Substrates of Complex Behaviors in C. elegans. Annual Review of Neuroscience. 28: 451-501.
Zheng, Y., Mellem, J.E., Brockie, P.J., Madsen, D.M., and Maricq, A.V. (2004) SOL-1 is a CUB-Domain Protein Required for GLR-1 Glutamate Receptor Function in C. elegans. Nature 427: 451-457.
Francis, M.M., Mellem, J.E., and Maricq, A.V. (2003) Bridging the gap between genes and behavior: recent advances in the electrophysiological analysis of neural function in Caenorhabditis elegans. Trends in Neurosciences 26: 90-99.
Mellem, J.E., Brockie, P.J., Zheng, Y., Madsen, D.M., and Maricq, A.V. (2002) Decoding of Polymodal Sensory Stimuli by Postsynaptic Glutamate Receptors in C. elegans. Neuron 36: 933-944.
Brockie, P.J., Mellem, J.E., Hills, T., Madsen, D.M., and Maricq, A.V. (2001) The C. elegans glutamate receptor subunit NMR-1 is required for slow NMDA-activated currents that regulate reversal frequency during locomotion. Neuron 31: 617-630.
1
| |
|
|
