Description of Research Expertise:
The primary interest of my laboratory program lies with the molecular and cellular pathophysiology of psychotic and mood disorders. Directing the Neuropsychiatric Signaling Program in the department of psychiatry, my research has a special focus on identifying intracellular and molecular alterations in neural tissues derived from patients and investigating their underlying mechanisms in animal and in vitro models. Examining molecular and cellular processes occurring in patients has been one of fundamental challenges in the field. In response, my laboratory has taken a path of developing new research paradigms to address questions that could not have been otherwise.
There are two lines of research paradigms that we have developed: analyses of subcellular proteome and intracellular signaling in postmortem brains and of olfactory neuroepithelial biopsy tissues derived from patients. Postmortem brain tissues may harbor biological characteristics linked to the subjects’ clinical profiles, but study of intracellular signaling in those tissues has been hampered. To that end, we have established a series of research paradigms to monitor receptor-mediated activation of intracellular signaling to isolate subcellular fractions enriched for post-synaptic density and synaptic membranes, to assess kinase activity in synaptic membranes and to capture protein complexes followed by mass spectrometer based quantitative proteomics. The olfactory neuroepithelial (OE) biopsy approach offers unique opportunities to obtain neural tissues of living patients that can be studied using ex vivo and in vitro paradigms. This paradigm permits us to address clinically relevant molecular and cellular mechanisms of neuropsychiatric illnesses, specifically pertinent to certain phase or state of illnesses. We have established olfactory neuroepithelial cell lines derived from more than 400 subjects with various psychiatric illnesses. Presently we examine these cells for various molecular pathways implicated for schizophrenia, bipolar disorder and depression using an induced neuronal cell paradigm.
1. Finding direct evidence for NMDAR hypofunction in schizophrenia and identifying molecular underpinnings. NMDAR hypofunction is a major pathophysiologic postulate for schizophrenia supported by genetic, pharmacologic and behavioral evidence. A bottleneck however had been that there had been no direct evidence supporting that NMDAR function is indeed decreased in schizophrenia. Using the newly devised postmortem methods described above, we found direct evidence for NMDAR hypofunction, namely decreased tyrosine phosphorylation of NR2 subunits. Subsequently, we found an underlying mechanisms for this dysregulation, Src hypoactivity.
1. Banerjee A, Wang H-Y, Borgmann-Winter KE, MacDonald ML, Stucky A, Kvasic J, James Kaprielian J, Ray R, Egbujo C, Talbot K, Hemby SE, Siegel SJ, Arnold SE, Sleiman P, Chang X, Hakonarson H, Gur RE, Hahn C-G. Src kinase as a mediator of convergent molecular abnormalities leading to NMDAR hypoactivity in schizophrenia. Mol Psychiatry. 2014 Oct 21. doi: 10.1038/mp.2014.
2. Hahn CG. A Src link in schizophrenia. Nat Med. 2011 Apr;17(4):425-427.
3. Hahn C-G, Wang, H., Cho D., Talbot K., Gur. R.E., Berrettini, W.H., Bakshi K., Kamins J., Borgmann-Wnter, K.E., Siegel, S.J., Gallop R.J. and Arnold, S.E. (2006) Abnormally enhanced neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nature Medicine, 12(7): 824-828.
2. Development of olfactory neuroepithelial biopsy research methods. Olfactory epithelial biopsy approach offers a unique opportunity to study neural cells derived from patients without genomic reprogramming. We have established several research paradigms, which have permitted us to study intracellular signaling and other neurobiological measures in neural cells from patients.
1. Borgmann-Winter, KE, Wang, H-Y., Ray, R., Willis, B., Moberg,P., Gur, R., Turetsky, B. Hahn, C-G. Altered G Protein Coupling in Olfactory Neuroepithelial Cells from Patients with Schizophrenia. Schizophrenia Bulletin (in press).
2. Egbujo CN, Sinclair D, Borgmann-Winter KE, Arnold SE, Turetsky BI, Hahn C-G. Molecular Evidence for decreased synaptic efficacy in the postmortem olfactory bulbs of individuals with schizophrenia. Schizophrenia Research. 2015 Aug 7 (Epub ahead of print).
3. Borgmann-Winter, KE, Willard, S, Sinclair, D, Mirza, N, Turetsky, B., Berretta, S. Hahn C-G. Translational Potential of Olfactory Neuroepithelium for the Study of Neuropsychiatric Illness. Translational Psychiatry. March 17, e527, 2015.
4. Hahn C-G, Han L-Y, Rawson N.E., Mirza N., Borgmann-Winter K.E., Lenox R.H. and Arnold S.E. (2005) In vivo and in vitro neurogenesis in human olfactory epithelium. J Comparative Neurology 483(2):154-63
5. Hahn C-G, Gomez G., Restrepo D., Friedman E., Josiassen R., Pribitkin E., Lowry L.D. and Rawson N. E. (2005) Aberrant intracellular calcium signaling in olfactory neurons from bipolar patients. Amer. J Psychiatry, 162(3):616-8.
3. Development of research paradigms in postmortem brain studies. Postmortem brains may harbor critical information pertinent to pathophysiology of brain disorders; yet most of the studies had been limited to expression analyses, i.e., protein or mRNA quantification. We have developed a series of methods towards the goal of assessment of intracellular signaling activity, intracellular trafficking of proteins and protein interactions. They include the postmortem brain receptor activation paradigm, in which intracellular signaling mechanisms are monitored in postmortem brain tissues (Hahn et al, 2006, Nature Medicine), recently biochemical fractionation and proteomic analyses of postmortem brains (Hahn et al, 2009, PLoS ONE) and SRM-LC-MS method (MacDonald, 2012). These methods are seen as highly novel and critical methods and are currently being used by several laboratories world wide.
1. Macdonald ML, Ciccimaro E, Prakash A, Banerjee A, Seeholzer SH, Blair IA, Hahn CG. (2012) Bioochemical Fractionation and Stable Isotope Dilution Liquid Chromatography-Mass Spectrometry for Targeted and Microdomain-Specific Protein Quantification in Human Postmortem Brain Tissue. Mol Cell Proteomics. PMID: 22942359
2. Hahn CG, MacDonald ML, Banerjee A, Cho D, Kamins J, Nie Z, , Grosser T, Borgmann-Winter KB, Angel Pizarro3, Eugene Ciccimaro5,Steven E. Arnold, Hoau-Yan Wang , I.A. Blair. The post-synaptic density of human postmortem brain tissues as a pathophysiologic study paradigm. PLoS One. 2009;4(4):e5251.
Turetsky Bruce I, Hahn Chang-Gyu, Arnold Steven E, Moberg Paul J: Olfactory receptor neuron dysfunction in schizophrenia. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 34 (3): 767-74,2009.
Borgmann-Winter K E, Rawson N E, Wang H-Y, Wang H, Macdonald M L, Ozdener M H, Yee K K, Gomez G, Xu J, Bryant B, Adamek G, Mirza N, Pribitkin E, Hahn C-G: Human olfactory epithelial cells generated in vitro express diverse neuronal characteristics. Neuroscience 158 (2): 642-53,2009.
McNamara Robert K, Hahn Chang-Gyu, Jandacek Ronald, Rider Therese, Tso Patrick, Stanford Kevin E, Richtand Neil M: Selective deficits in the omega-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder. Biological psychiatry 62 (1): 17-24,2007.
Hahn Chang-Gyu, Wang Hoau-Yan, Cho Dan-Sung, Talbot Konrad, Gur Raquel E, Berrettini Wade H, Bakshi Kalindi, Kamins Joshua, Borgmann-Winter Karin E, Siegel Steven J, Gallop Robert J, Arnold Steven E: Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nature medicine 12 (7): 824-8,2006.
Hahn Chang-Gyu, Umapathy, Wang Hoau-Yan, Koneru Ramesh, Levinson Douglas F, Friedman Eitan: Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients. Journal of psychiatric research 39 (4): 355-63,2005.
Hahn Chang-Gyu, Gomez George, Restrepo Diego, Friedman Eitan, Josiassen Richard, Pribitkin Edmund A, Lowry Louis D, Gallop Robert J, Rawson Nancy E: Aberrant intracellular calcium signaling in olfactory neurons from patients with bipolar disorder. The American journal of psychiatry 162 (3): 616-8,2005.
Hahn Chang-Gyu, Han Li-Ying, Rawson Nancy E, Mirza Natasha, Borgmann-Winter Karin, Lenox Robert H, Arnold Steven E: In vivo and in vitro neurogenesis in human olfactory epithelium. The Journal of comparative neurology 483 (2): 154-63,2005.
Talbot Konrad, Eidem Wess L, Tinsley Caroline L, Benson Matthew A, Thompson Edward W, Smith Rachel J, Hahn Chang-Gyu, Siegel Steven J, Trojanowski John Q, Gur Raquel E, Blake Derek J, Arnold Steven E: Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. The Journal of clinical investigation 113 (9): 1353-63,2004.
Arnold S E, Han L Y, Moberg P J, Turetsky B I, Gur R E, Trojanowski J Q, Hahn C G: Dysregulation of olfactory receptor neuron lineage in schizophrenia. Archives of general psychiatry 58 (9): 829-35,2001.