Adult Neurogenesis in Neuropsychiatric Disease

Francis Szele

University of Oxford

Funded in September, 2011: $200000 for 2 years
LAY SUMMARY . BIOGRAPHY .

LAY SUMMARY

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Altered production and migration of new brain cells may contribute to psychiatric diseases

Investigators will study whether excessive development and altered migration of new neurons in the brain contributes to schizophrenia and to other psychiatric disorders.

            Scientists have established that the brain continues to make new neurons throughout life, through a process called neurogenesis. Neural stem cells (called neuroblasts) reside in a region located toward the back of the brain, called the subependymal zone (SEZ).  When the brain needs new cells, the neuroblasts migrate into the olfactory bulb, a region that facilitates the sense of smell.  Here the neuroblasts mature into neurons and then migrate into other brain areas that need them. Ordinarily, neural stem cell activation in the SEZ is regulated, at least in part, by “ependymal” cells that are located just above the SEZ. 

            Recently, investigators found preliminary evidence in autopsy studies of brain tissues from deceased schizophrenia patients that regulatory ependymal cells are reduced and neurogenesis is increased. Similarly, increased neurogenesis has been observed in autopsied brain tissues from patients who had died following Alzheimer’s and Huntington’s disease, both of which have psychiatric aspects. Moreover, a number of genes and molecules that affect neurogenesis have been implicated in psychiatric disorders. Signaling disruptions in several neurotransmitters, for instance, are seen both in psychiatric diseases and in disorders that affect adult neurogenesis. Additionally, olfactory deficits occur both in schizophrenia and Alzheimer’s disease. These findings suggest a link between adult neurogenesis and psychiatric diseases. Additional evidence suggests that maintenance of normal neurogenesis is necessary for anti-depressive medication effectiveness.

Based on these related factors, the investigators hypothesize that the adult SEZ and neurogenesis are altered in psychiatric diseases, and that alterations may occur differently in different psychiatric diseases, potentially serving as biomarkers for testing treatments. They will explore these hypotheses by studying neurogenesis in autopsied brain tissues from patients who had schizophrenia and compare them to autopsied tissues of three other categories: patients who had unipolar depression, bipolar disease, or no psychiatric disease. The study must be undertaken in brain tissues because current techniques, including MRI, cannot adequately show stem cell neurogenesis in living people.  They will measure the integrity and density of ependemyal cells, and of the cells involved in neurogenesis, and determine whether altered regulation, development, and migration occurred and whether these differences vary among the three psychiatric diseases. 

Significance: If this study identifies how altered neurogenesis occurs and varies among schizophrenia, unipolar depression, and bipolar disease, the findings could produce new biomarkers that could be used to test new therapeutic agents for each.

INVESTIGATOR BIOGRAPHIES

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Francis Szele

Principal Investigator/Program Director (Last, First, Middle):    Szele, Francis

 

 

B I OG RA P H I CA L SKETCH

Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2.

Follow this format for each person. DO NOT EXCEED FOUR PAGES.

 


NAME

Szele, Francis G., PhD

 

eRA COMMONS USER NAME

FGSZELE


POSITION TITLE

University Lecturer

Department of Physiology, Anatomy and Genetics


 

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)

 

INSTITUTION AND LOCATION

DEGREE

(if applicable)

YEAR(s)

FIELD OF STUDY

College of William and Mary, VA University of Pennsylvania, PA Harvard Medical School, MA

B.S. Ph.D. Postdoc

1985

1994

1999

Biology Neurobiology Developmental Biology

 

A .  Positions and Honors.

 

P o sitions

1985 - 1987          Biologist, Laboratory of Clinical Science, NIMH, NIH, Bethesda, MD

 

 

1990 - 1994                Ph.D., Dept. of Pharmacology, Chesselet Laboratory, University of Pennsylvania, Philadelphia, PA

 

1994 – 1999               Postdoctoral Fellow, Cepko Laboratory, Department of Genetics, Harvard Medical School, Boston, MA

 

1999 – 2007         Assistant Professor, Dept. of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL

 

 

2007 – present     University Lecturer, Department of Physiology, Anatomy and Genetics & Tutorial

Fellow, St. Anne’s College, University of Oxford, UK

 

 

Hon o rs

2001           Searle Junior Fellow, Searle Center for Teaching Excellence, Northwestern University.

2002           Dept of Pediatrics Faculty Award for Extraordinary Contributions to the Dept’s Missions.

2004           Recepent of Bernard L. Mirkin Research Scholar Endowed Chair.

2008           Junior Pro-Proctor, University of Oxford.

 

 

B .  Selected peer-reviewed publications (in chronological order).

 

Szele F.G . and Pritchett D.B.: High affinity agonist binding to cloned 5-Hydroxytryptamine2 receptor is not sensitive to GTP analogs. Molecular Pharmacology 43: 915-920, 1993.

 

Szele F.G. , Alexander C., and Chesselet M-F.: Expression of molecules associated with neuronal plasticity in the striatum after aspiration and thermocoagulatory lesions of the cerebral cortex in adult rats. Journal of Neuroscience 15: 4429-4448, 1995.


 

Szele F.G. and Chesselet M-F.: Cortical lesions induce an increase in cell number and PSA-NCAM expression in the subventricular zone of adult rats. Journal of Comparative Neurology 368: 439-454, 1996.

 

Szele F.G. and Cepko C.L.: A subset of clones in the chick telencephalon arranged in rostrocaudal arrays.

C urrent Biology  6: 1685-1690, 1996.

 

Szele F.G . and Cepko C.L.: The dispersion of clonally related cells in the developing chick telencephalon.

D evelopmental Biology 195: 100-113, 1998.

 

Goings G.E., Wibisono B.L., and Szele F.G.: Cerebral cortex lesions decrease the number of BrdU-positive subventricular zone cells in mice. Neurosci. Lett. 329: 161-164, 2002.

 

Goings G.E., Sahni  V., and Szele F.G.: Migration patterns of subventricular zone cells in adult mice change after cerebral cortex injury. Brain Res. 996: 213-226, 2004.

 

Sundholm-Peters N.L., Yang H.K.C., Goings G.E., Walker A.S., and Szele F.G.: Radial glia-like cells at the base of the lateral ventricles in adult mice. J. Neurocytol. 33: 153-164, 2004.

 

Yang H.K.C., Sundholm-Peters N.L., Goings G.E., Walker A.S., Hyland K., and Szele F.G.: Distribution of doublecortin expressing cells near the lateral ventricles in the adult mouse brain.

J . Neurosci. Res. 76: 282-295, 2004.

 

Ramaswamy S., Goings G.E., Soderstrom K.E., Szele F.G., Kozlowski D.A.: Cellular proliferation and migration following a controlled cortical impact in the mouse. Brain Res. 1053: 38-53, 2005.

 

Sundholm-Peters N.L., Yang H.K.C., Goings G.E., Walker A.S., and Szele F.G.: Subventricular zone neuroblasts emigrate towards cortical lesions. J. Neuropath. Exp. Neurol. 64:1089-1100, 2005.

 

Gwendolyn E. Goings, Dorothy A. Kozlowski, and Szele F.G. Differential activation of microglia in neurogenic versus non-neurogenic regions of the forebrain. Glia, 54: 329-342, 2006.

 

Maria L.V. Dizon, Laura Shin, Nikki L. Sundholm-Peters, Edward Kang, and Szele F.G. Subventricular zone cells remain stable in vitro after brain injury. Neuroscience, 142: 717-725, 2006.

 

Ocbina, P.J., L. Shin, M.L. Dizon, and Szele F.G., Doublecortin is necessary for the migration of adult subventricular zone cells from neurospheres. Molecular and Cellular Neuroscience, 33: 126-135, 2006.

 

Nam S.C., Kim Y., Dryanovski D., Walker A., Goings G., Woolfrey K., Kang S.S., Chu C., Chenn A., Erdelyi F., Szabo G., Hockberger P., Szele F.G. Dynamic features of postnatal subventricular zone cell motility: A two- photon time-lapse study. J Comp Neurol 505:190-208, 2007.

 

Goings G. E., Greisman A., James R., Abram L., Smith-Begolka W., Miller S.D. and Szele F.G. Hematopoietic cell activation in the subventricular zone after Theiler’s virus infection. J. Neuroinflammation. 5: 44-66. 2008.

 

Kim Y., Comte I., Szabo G., Hockberger P. and Szele F.G. Adult mouse subventricular zone stem and progenitor cells are sessile and epidermal growth factor receptor negatively regulates neuroblast migration. PloS One 4: 8122-8135, 2009.

 

Kim Y.,  Wang W-Z., Comte I., Pastrana E., Tran P.B., Brown J., Miller R.J., Doetsch F., Molnár Z. and Szele F.G. Dopamine stimulation of postnatal murine subventricular zone neurogenesis via the D3 receptor. J. Neurochem. 114: 750-760, 2010.

 

Martinez-Molina N., Kim Y., Hockberger P. and Szele F.G< Rostral Migratory Stream Neuroblasts Turn and

Change Directions in Stereotypic Patterns. Cell Adhes and Migrat 5: 83-95 2011.


 

 

Comte I., Kim Y., Young C.C., van der Harg J.M., Hockberger P., Bolam P.J., Poirier F. and Szele F.G.

Galectin-3 maintains cell motility from the subventricular zone to the olfactory bulb. J Cell Sci In Press 2011.

 

 

 

C. Research Support

 

 

Previous Research Support

 

 

2001 – 2006         “Response of the Subventricular Zone to Brain Injury” R01 NS042253-04, NIH, NINDS Role: PI $600,000.

 

2002 – 2006         “Imaging Subventricular Zone Cell Migration With Time-Lapse Multiphoton Microscopy” CMRC Seed Grant , Internal; State of Illinois Excellence in Academic Medicine Role: PI $34,000.

 

2005 – 2006           “Subventricular Zone (SVZ) to Brain Injury Response” CMRC Bridge Grant Institutional Award. Role: PI $100,000.

 

2006 - 2008           “Are there stem cells in the adult brain?” Illinois Regenerative Medicine Institute, Role: Co-PI. $85,978.

 

2007 - 2010           “Two photon time-lapse microscopy of subventricular zone stem cell migration”. John

Fell Research Fund, University of Oxford. Role: PI. £93,857.

 

 

2008 - 2009          “MRI of subependymal zone stem cells in traumatic brain injury”  Oxford Stem Cells

Institute. Role: PI. £10,000.

 

 

2008 to 2009         “Imaging cellular and molecular processes driving cell migration during development” BBSRC Research Equipment Initiative Grant Role: Co-PI. £237,000.

 

2009 - 2010          Wellcome Trust Value in People. Role: PI. £35,000.

 

 

 

Ongoing Research Support

 

2006 – 2011        “Subventricular zone cell migration after injury”NIH, NINDS, RO1 NS051594-01

Role: PI, $1,125,000.

 

 

2010 - 2011          “iPS cells from schzophrenics to probe neural development.” Oxford Stem Cells

Institute. Role: PI. £10,000.

 

 

2010 - 2011          “Adult Subventricular Zone Neurogenesis in Preclinical Models of Schizophrenia’.

Oxford University/McGill University Collaborative Award. Role: Co-PI £8,000.

 

 

 

Pending Research Support

 

 

2011 – 2012         “Increasing endogenous dopaminergic neurogenesis for Parkinson’s disease”Parkinson’s UK Innovation Grant. Role: PI. £35,000