Key Laboratory Personnel:
Attila Szebeni, M.S.; Lab Coordinator
Katalin Szebeni, M.D.; Assistant Professor
Michelle Chandley, Ph.D.; Research Associate
Erich Lutz, Honors student
Research Interests:
My principal area of research is the study of the biological
basis of clinical depression and the molecular mechanisms of
antidepressant drugs. To study depression biology, we utilize
brain tissue from humans who have either committed suicide or
have died from accidental or natural causes, all of whom have
had psychiatric diagnoses made post-mortem using a rigorous
retrospective psychological examination through first-degree
family members. Brain tissues are studied at the cellular and
molecular level in an attempt to understand the relationship
between brain biology and psychiatric illnesses that lead to
suicide, particularly depressive disorders.
My laboratory has discovered specific
protein and gene expression abnormalities in discrete areas
of the human brain, i.e. the noradrenergic locus coeruleus
and the amygdala, that are associated with severe depression.
Recent findings by other laboratories have demonstrated that
glia in several areas of the brain are reduced in clinical
depression. These glial findings are intriguing because
glia and noradrenergic neurons have a very special and
intimate relationship. In some areas of the brain,
noradrenergic neurons make contacts solely with glia and not
with other neurons. Glia express receptors for
norepinephrine and communicate to noradrenergic neurons via a
variety of gliotransmitters, including cytokines and growth
factors. Hence, our current research is focusing on the
bi-directional communication between glia and noradrenergic
neurons in depression, and its modulation by antidepressant
drug action.
Using gene expression analysis, we are studying this
neuron-glial communication in human postmortem brains, in
animal models of depression and antidepressant drug action,
and in cell culture systems. For some of this work, we
use a combination of laser capture microdissection and
quantitative PCR methods.
Laser capture microdissection/PCR allows us to study gene
expression in specific types of neurons and glia (astrocytes,
oligodendrocytes, microglia) captured individually from human
and rodent brains. The discovery of cell specific gene
expression changes in depression, paralleled by
investigations of how the expression of these specific genes
are modulated by antidepressant drug treatment in animal
models, has the potential to lead us to new antidepressant
drug targets and novel treatment strategies for depressive
disorders.
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My research is currently funded by National Institute of
Mental Health (MH46692), the American Foundation for Suicide
Prevention, and Sepracor, Inc.
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Selected Publications:
Klimek V., Stockmeier C.A., Overholser J., Meltzer H.Y.,
Kalka S., Dilley G. and Ordway G.A.: Reduced levels of
norepinephrine transporters in the locus coeruleus in major
depression. J. Neurosci. 17:8451-8458, 1997.
Zhu M.-Y., Blakely R.D. Apparsundaram S., and Ordway G.A.:
Downregulation of the human norepinephrine transporter in
intact 293-hNET cells exposed to desipramine. J.
Neurochem. 70:1547-1555, 1998.
Zhu M.-Y., Klimek V., Dilley G.E., Haycock J.W., Stockmeier
C.A., Overholser J.C., Meltzer H.Y. and Ordway
G.A.: Elevated levels of tyrosine hydroxylase in the
locus coeruleus in major depression. Biol. Psychiatry,
46:1275-1286, 1999.
Zhu M.-Y., Shamburger S., Li J. and Ordway G.A.: Regulation
of the human norepinephrine transporter by cocaine and
amphetamine. J. Pharmacol. Exp. Therap., 295:951-959, 2000.
Klimek V., Zhu M.-Y., Dilley G., Konick L., Overholser J.,
Meltzer H.Y., May W.L., Stockmeier C.A., and Ordway G.A.:
Effects of long-term cigarette smoking on the human locus
coeruleus. Arch. Gen. Psychiatry., 58:821-827, 2001.
Klimek V., Schenk J.E., Han H., Stockmeier C.A. and Ordway
G.A.: Dopaminergic abnormalities in amygdaloid nuclei in
major depression. A postmortem study. Biological
Psychiatry 52:740-748, 2002.
Ordway G.A., Klimek V. and Mann J.J.: Neurocircuitry of
mood disorders. In: Psychopharmacology. The Fifth Generation
of Progress. (K.L. Davis, D. Charney, J.T. Coyle, C.
Nemeroff, eds) Lippincott-Williams & Wilken, pp.
1051-1064, 2002.
Zhang W. and Ordway G.A. The alpha2C-adrenoceptor modulates
GABA release in mouse striatum. Mol. Brain Res., 112:24-32,
2003.
Karolewicz B., Szebeni K., Stockmeier C.A., Konick L.,
Overholser J.C. Jurgis G., Roth B.L., and Ordway G.A.:
Low nNOS protein in the locus coeruleus in major
depression. J. Neurochem., 91:1057-1066, 2004.
Karolewicz B., Stockmeier C.A., and Ordway G.A.:
Elevated levels of the NR2C subunit of the NMDA receptor in
the locus coeruleus in depression.
Neuropsychopharmacology, 30:1557-67, 2005.
Recent publications
Karolewicz B., Szebeni K., Gilmore T., Maciag D., Stockmeier
C.A. and Ordway G.A. Elevated levels of NR2A and PSD-95
in the lateral amygdala in depression. Int. J.
Neuropsychopharmacology, 23:1-11, 2009.
Ordway G.A., Szebeni A., Duffourc M.M., Dessus-Babus
S. and Szebeni K.: Gene expression analyses of neurons,
astrocytes, and oligodendrocytes isolated by laser capture
microdissection from human brain: Detrimental effects of
laboratory humidity. J. Neurosci. Res., 87:2430-2438,
2009.
Karolewicz B., Johnson L., Szebeni K., Stockmeier C.A., and
Ordway G.A.: Glutamate signaling proteins and tyrosine
hydroxylase in the locus coeruleus of alcoholics. J. Psych.
Res., 42:348-355, 2008.
Zhu M.-Y., Wang W.-P., Cai Z.-W., Regunathan S., and Ordway
G.A.: Exogenous agmatine has neuroprotective effects against
restraint-induced structural changes in the rat brain. Europ.
J. Neurosci. 27:1320-1332, 2008.
Xiang L., Szebeni K., Szebeni A., Klimek V., Stockmeier,
C.A., Karolewicz B., Kalbfleisch J. and Ordway, G.A.:
Dopamine receptor gene expression in human amygdaloid nuclei:
elevated D4 receptor mRNAs in depression. Brain Res.
1207:214-224, 2008.
Karolewicz B., Szebeni K., Gilmore T., Maciag D., Stockmeier
C.A. and Ordway G.A. Elevated levels of NR2A and PSD-95 in
the lateral amygdala in depression. Int. J.
Neuropsychopharmacology, 23:1-11, 2008.
Karolewicz B., Szebeni K., Gilmore T., Maciag D., Stockmeier
C.A. and Ordway G.A. Elevated levels of NR2A and PSD-95 in
the lateral amygdala in depression. Int. J.
Neuropsychopharmacology, 23:1-11, 2009.
Ordway G.A., Szebeni A., Duffourc M.M., Dessus-Babus S. and
Szebeni K.: Gene expression analyses of neurons, astrocytes,
and oligodendrocytes isolated by laser capture
microdissection from human brain: Detrimental effects of
laboratory humidity.
J. Neurosci. Res., 87:2430-2438, 2009.
Books
Ordway, G.A., Schwartz, M. and Frazer
A.: Brain Norepinephrine: Neurobiology and
Therapeutics, Cambridge University Press, 2007.
Click here for printable version
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