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Biological Sciences Department Faculty
Postdoctoral Research Fellow, Dept. of Biology University of Utah, 1999
Ph.D. University of Washington, 1994
B.Sc. University of Calgary, 1987
REGULATION OF GABA SYNAPSE STRENGTH
What controls the strength of a synapse? This is a central question in neuroscience. The strength of individual synapses determines the balance between neuronal excitation and inhibition, which is critical for the function of all circuits in the brain. My overall research goal is to understand how synapse strength is initially set in development, and how it undergoes change in the mature nervous system. My specific interests focus on inhibitory synapses. They are essential for healthy brain function, and inhibitory synapse defects lead to epilepsy and anxiety disorders. The GABAA receptor, a ligand-gated chloride channel of the cys-loop super¬family, is the principal inhibitory receptor. The abundance and sensitivity of synaptic GABAA receptors are the principal determinants of inhibitory synapse strength. The mechanisms that regulate GABAA receptors are not well understood, principally because GABA synapses in the mammal are complex and difficult to access experimentally.
To advance our understanding of GABA synapses, there is a need for a simple experimental model system. I have been developing such a system by studying GABA synapses in the nematode Caenorhabditis elegans, a genetically-tractable model organism. In C. elegans we can manipulate protein structure and expression in the postsynaptic cells, or in the presynaptic neurons that innervate them. We can analyze synapse morphology by imaging presynaptic and postsynaptic marker proteins with fluorescence and electron microscopy, and we can analyze synapse function using patch-clamp electrophysiology. Most importantly, we can study synapses in vivo, in intact animals where development has taken place normally, and the connections between neurons and their targets are intact. As with any biological pathway, there is a high likelihood that the basic mechanisms of GABAA receptor regulation will be conserved between C. elegans and mammals. As a postdoctoral fellow, I cloned and characterized the C. elegans GABAA receptor. As a Research-Track Assistant Professor, I have developed three approaches to understand the regulation of that receptor: synapse development, regulation of GABAA receptor abundance at synapses, and regulation of GABAA receptor function. This research forms the basis of my future work:
1. GABA synapse development and autophagy: To understand GABA synapse development, we deprived postsynaptic cells of their
presynaptic inputs. We determined that presynaptic contact is required to stabilize GABAA receptors on the postsynaptic cell
surface (Rowland et
al. 2006, J. Neurosci 26:1711). Other¬wise, GABAA receptors traffic to autophagosomes, and then to the lysosome for degrad¬ation.
This result is
novel: stabilization of surface GABAA receptors by presynaptic contact had not been previously described, and degradative
trafficking of GABAA
receptors by autophagy was unknown. I plan to study the cell-cell interaction between neurons and muscles that controls GABAA
using genetic and molecular approaches.
2. Regulation of synaptic GABAA receptor levels: My lab has developed the skills to measure the levels of endo¬genous GABAA receptors at C. elegans synapses, using a combination of quantitative immunofluor¬escence and patch-clamp muscle recordings in cut-open worms. We have shown that the C. elegans GABAA receptor, like the mammalian, is subject to homeostatic regulation, and that calcium signaling and the lysosomal degradation are involved. I will continue to analyze mutant worms with cell-signaling and trafficking defects, including autophagy-defective worms, to identify the genetic pathways that control GABAA receptor synaptic levels and homeostasis.
3. GABAA receptor function: Neurosteroid regulation: Modulation of GABAA receptor function by drugs is an important strategy to treat neurological disorders. We have used the C. elegans GABAA receptor to identify a new site of action for such drugs (Wardell et al. 2006, Brit. J. Pharm. 148:162). This site is important because it is utilized by endogenous neuromodulatory steroids. I will further study this site using high-resolution kinetics analysis, and translate those findings to the human GABAA receptor by mutating the homologous residues and analyzing receptor pharmacology and kinetics.
Combined, these three approaches make up an integrated analysis of the mechanisms that regulate GABA synapse strength in C. elegans. Given the high likelihood of conservation, the results of these experiments will provide many interesting hypotheses to test in the mammalian brain.
Bamber, B. A., Beg, A. A., Twyman, R. E. and Jorgensen, E. M. (1999). The Caenorhabditis elegans unc-49 locus encodes multiple
subunits of a
heteromultimeric GABA receptor. J. Neurosci. 19, 5348-5359.
Zhen, M., Huang, X., Bamber, B. A., and Jin. Y. (2000). Regulation of presynaptic terminal organization by C. elegans RPM-1, a putative guanine nucleotide exchanger with a Ring-H2 finger domain. Neuron 26, 331-343.
Bamber, B. A., Twyman, R. E., and Jorgensen, E. M. (2003). Pharmacological characterization of the homomeric and heteromeric UNC-49 GABA receptors in C. elegans. British Journal of Pharmacology 138: 883-893.
Bamber, B. A., Richmond, J. E., and Jorgensen, E. M. (2005) The synaptic GABA receptor at the C. elegans neuromuscular junction contains UNC-49B and UNC-49C. British Journal of Pharmacology 144: 502-509.
Wardell B., Marik P. S., Piper D., Rutar T., Jorgensen E. M., Bamber B. A. (2006) Residues in the first transmembrane domain of the Caenorhabditis elegans GABAA receptor confer sensitivity to the neurosteroid pregnenolone sulfate. British Journal of Pharmacology 148: 162-172
Rowland, A. M., Olsen, J. G., Hall, D. H., Richmond, J. E. and Bamber, B. A. (2006) Presynaptic terminals independently regulate synaptic clustering and autophagy of GABAA receptors in Caenorhabditis elegans. J. Neurosci. 26:1711-1720.
Bamber, B. A. and Rowland, A. M. (2006) Shaping cellular form and function by autophagy. Autophagy 2:247-249.