One of the most distinctive features of the human brain is the expansive size of the cerebral cortex relative to subcortical areas. The prefrontal areas of the cortex control how we deal with internal and environmental stimuli, by carrying out a cluster of cognitive behaviors called 'executive functions.' These faculties enable individuals to focus, act appropriately, plan and achieve goals, adapt to change, and integrate new information. The performance of executive functions is regulated by neuromodulators such as dopamine, norepinephrine, and serotonin. Further, executive functions are compromised to varying degrees in a number of mental illnesses including schizophrenia, attention deficit hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD). Interestingly, each of these neuropsychiatric disorders exhibits a substantial level of heritability. However, the etiologies are complex involving a genetic predisposition accounted for by multiple susceptibility loci each contributing a small increase in risk, as well as environmental modifiers.
Research in our laboratory is focused on understanding the molecular mechanisms by which neuromodulators regulate the prefrontal cortex activity and executive functions. We are taking proteomics approaches to defining the gene products involved in the neuromodulation of prefrontal cortex. We are further characterizing the role of these proteins in mechanistic detail at the behavioral, physiological and molecular levels using a variety of experimental approaches involving transgenic mice as well as heterologous systems. With collaborators, we are also investigating whether expression of these regulatory proteins is altered in schizophrenia, and identifying polymorphisms (common genetic variants). By doing so, we hope to learn whether alleles of the genes under study might lead to maladaptive executive functions. Whether candidate alleles actually confer increased risk for developing schizophrenia can be tested in genetic association studies. We hope that these lines of investigation will provide greater insight into the etiology or pathology of schizophrenia, and thereby aid in the development of better preventive or treatment strategies.
NIMH P50 MH44866
Role on Project: Co-Principal Investigator
"Calcium Signaling & Prefrontal Function in Schizophrenia"
A growing body of evidence suggests that abnormal D1-like (D1R and D5R) dopamine (DA) receptor function in the prefrontal cortex contributes to the cognitive deficits observed in schizophrenia, but genetic studies have yet to identify risk alleles in either the D1 or D5R genes. We are exploiting recent advances in proteomics and bioinformatics to more fully elucidate the array of proteins associated with D1 and D5R signaling complexes in brain. Determining the protein composition of the D1 and D5R signaling complexes may in fact reveal new molecular targets for drug development strategies, and provide a fruitful strategy for identifying previously unknown candidate schizophrenia susceptibility genes.
Calcyon is a protein that regulates D1R surface expression and signaling and which co-localizes with D1Rs in prefrontal cortex. It turns out that calcyon interacts with clathrin light chain and stimulates clathrin mediated endocytosis in neurons. Recent genetic and postmortem studies link alterations in calcyon with ADHD and schizophrenia. We have developed transgenic mice that either over-express calcyon in forebrain (OE mice) or with a deletion of the calcyon gene (KO mice). We are testing the calcyon OE and KO mice on a battery of behavioral assays of prefrontal cortical functions. If performance deficits are detected, the calcyon KO or OE mice could serve as a tractable system with which to better characterize the etiology and resulting pathophysiology of schizophrenia. For example, the calcyon mice would provide a 'predisposed' genetic background in which to test the potentially detrimental effects of other putative heritable and environmental risk factors, as well as to test the effectiveness of newly developed drugs for ameliorating the currently treatment-refractory negative symptoms of schizophrenia.
In the CNS, clathrin mediated endocytosis is crucial for efficient synaptic transmission. Projects are ongoing in the lab to examine clathrin-mediated synaptic adaptations in neocortical and DA neurons of the calcyon KO and OE using electrophysiological and cell biological approaches.
Heather T. Davidson, Postdoctoral Fellow
Jiping Xiao, Graduate Student, Pharmacology and Toxicology
Nagendran Muthusamy, Graduate Student, Neuroscience
Yali Hou, Research Associate II
-
1979 - Summa cum Laude, M.J. Polisuk Prize in Biochemistry, McGill University
-
1992 - NIMH Research Service Award
-
1994-1996 - NARSAD Young Investigator Award
-
1997-1999 - NARSAD Young Investigator Award
-
1998 - Dopamine '98 (IUPHAR Satellite Meeting) Strausbourg, France: Best Poster
-
2000 & 2003 - Department of Pharmacology and Toxicology Faculty Research Award
NARSAD Scientific Symposium, New York, NY, October 1995.
NIMH Neuroscience Center at St. Elizabeth's Hospital, February 1996.
Dept. of Neurobiology and Physiology, Northwestern University, February 1996.
Dept. of Pharmacology, University of Pennsylvania, April 1996.
Dept. of Pharmacology, Emory University, February 1997.
Dept. of Neurobiology, University of Pittsburgh School of Medicine, February 1997.
Dept. of Pharmacology, Columbia University, March 1997.
Dept. of Pharmacology and Toxicology, University of Kansas, April 1997.
Section of Neurobiology, Yale University, May 1997.
NIMH Center Director's Meeting, Washington, DC, July 1999.
Max Planck Institute for Psychiatry Symposium, Munich, Germany, November 1999.
Department of Cell Biology and Anatomy, Medical College of Georgia, February 2000.
Department of Biochemistry, Medical College of Georgia, March 2000.
Astra-Zeneca Pharmaceuticals, Worcester, MA, April 2000.
Dept. of Cell and Molecular Physiology, University of North Carolina, May 2000.
2nd Annual Great Lakes G-Protein Coupled Receptor Retreat, Ontario, October 2000.
Dept. of Pyschology, University of Georgia at Athens, November 2000.
Grand Rounds, Dept. of Psychiatry, Medical College of Georgia, November 2000 .
American College of Neuropsychopharmacology, San Juan, P.R., December 2000.
Commencement Address, Catherine McAuley High School, Portland, ME, May 2001.
IBC GPCR Conference, Scottsdale, Arizona, June 2001
8th International Conference on Peripheral Dopamine, Stockholm, Sweden, June 2002.
3rd Forum of the European Neuroscience Societies, Paris, France, July 2002.
Emory University, Dept. of Neurology, November 2002
Southeast Conference of American Chemical Society: Symposium on Calcium Signaling in Biology, October 2003.
Geisinger Health Systems/Weis Center for Research, Danville Pennsylvania, May 6, 2004.
Wenner-Gren Symposium on 'Receptor-receptor interactions among heptaspaning membrane receptors: From structure to function. Stockholm, Sweden, September 8, 2004.
(10 plus pubmed link)
Lezcano, N., Mrzljak, L., Eubanks, S., Levenson, R., Goldman-Rakic, P., Bergson, C. (2000) Dual Signaling Regulated by Calcyon, a D1 Dopamine Receptor Interacting Protein. Science 287, 1660-1664.
Lidow, M. S., Roberts, A., Zhang, L., Lezcano, N. and Bergson, C. (2001) G protein-coupled Receptor Cross-talk Protein, Calcyon, Regulates D1 Dopamine Receptor Agonist Affinity State. European Journal of Pharmacology. 427(3): 187-93
Wang, Q., Jolly, J. P., Lidow, M. S., Surmeier, J. D., Mullah, B. M., Bergson, C.and Robishaw, J. (2001) Dependence of D1 Dopamine Receptor Activation on G Protein g7 Subunit. J. of Biological Chemistry. 276(42): 39386-93
Lezcano, N. and Bergson, C. (2002) D1/D5 Dopamine Receptors Stimulate Intracellular Calcium Release in Neocortical and Hippocampal Neurons. J. of Neurophysiology 87, 2167-2175.
Koh, P.O., Bergson, C. Undie, A. S., Goldman-Rakic, P. S. and Lidow, M. S. (2003) Upregulation of the D1 Dopamine Receptor-Interacting Protein Calcyon in Schizophrenia. Archives of General Psychiatry 60, 311-319.
Dai, R. and Bergson, C. (2003) Genomic Structure and Expression of the Murine Calcyon Gene. Gene 311, 111-7.
Bergson, C., Levenson, R., Goldman-Rakic, P. S., and Lidow, M. S (2003) Dopamine Receptor Interacting Proteins: The Ca2+ Connection in Dopamine Signaling. Trends in Pharmacological Sciences 24, 486-92.
Ali,M.K. and Bergson, C. (2003) Elevated Intracellular Calcium triggers Recruitment of Calcyon to the Plasma membrane. Journal of Biological Chemistry 278, 51654-63.
Zhang, L., Bai, J., Undie, A.S., Bergson, C. and Lidow, M. (2005) D1 Dopamine Receptor Regulation of the Levels of the Cell-cycle-controlling Proteins, Cyclin D, P27 and Raf-1, in Cerebral Cortical Precursor Cells is Mediated Through cAMP-independent Pathways. Cerebral Cortex 15,74-84.
Dai, R., Ali, M.K., Xiao, J., Lezcano, N. and Bergson, C. (submitted) Mechanisms Underlying Gs-Gq Coupled GPCR Crosstalk
Xiao, J., Dai, R. and Bergson, C. (submitted) Interaction of Calcyon with Clathrin Light Chain Regulates Clathrin Mediated Endocytosis in Neurons.
Xiao J, Dai R, Negyessy L, Bergson C. Related Articles, Links Calcyon, a novel partner of clathrin light chain, stimulates clathrin-mediated endocytosis. J Biol Chem. 2006 Jun 2;281(22):15182-93.
|
