Sherry Leonard, Ph.D.
(303) 315-8412 and (303) 724-4426
Sherry.Leonard@UCHSC.eduDr. Leonard’s research is focused on the molecular neurobiology of neuronal nicotinic acetylcholine receptors in both nicotine addiction and schizophrenia, a common mental illness. The two subjects are intimately related as smoking is significantly elevated in the mentally ill and nicotinic receptors have been associated with a sensory processing deficit in schizophrenia. An impaired capacity to filter or gate auditory stimuli is seen in schizophrenia and this defect can be assayed by EEG. The gating deficit is inherited, being found in about ½ of the first degree relatives of schizophrenics who do not have the disease. This endophenotype, thus, represents a predisposition factor for schizophrenia. Study of such phenotypes in complex diseases can often simplify both the neurobiology and the genetics. The gating deficit is normalized by nicotine in both schizophrenics and in non-gating first degree relatives of schizophrenics. The auditory evoked potential deficit can be reproduced in laboratory animals where invasive, pharmacological experiments can be performed. The administration of antagonists of the a7 nicotinic receptor, including a-bungarotoxin and antisense oligonucleotides, blocks function of the a7 receptor and causes the animal to lose the capacity to filter out extraneous noise, similar to the phenotype we see in schizophrenia. Expression of the a7 nicotinic receptor is decreased in the hippocampus of schizophrenics, compared to controls and is differentially regulated by smoking in control and schizophrenic subjects. We have cloned a human cDNA for the a7 gene and have isolated a genomic clone. Mutation screening in the gene has revealed functional polymorphisms in the promoter region of the gene that appear to affect transcription. These mutations are associated with schizophrenia and also with the sensory gating deficit. We have also recently found that the a7 gene is partially duplicated in all subjects and the duplication is expressed as mRNA. Experiments are underway to study the function of this new transcript and to compare its expression in schizophrenic and control subjects.
Our laboratory also is involved with the effects of stress on gene expression. DNA/protein interactions are being studied for the ?7 nicotinic receptor gene following treatment with stress steroids. Microarray experiments will measure the effect of prenatal stress on global gene expression, which will be confirmed by QRT-PCR and protein analysis. In other microarray work ongoing in the lab we are comparing gene expression in human postmortem brain of smokers and non-smokers, and in the mentally ill..
Recent Publications:1. Judith Gault, Ralph Berger, Misi Robinson, Carla Drebing, Judith Logel, Jan Hopkins, Ted Moore, Suzette Jacobs, Jennifer Merriwether, Mun Jun Choi, EJ Kim, Katie Walton, Ashley Davis, Charles Breese, Robert Freedman, Sherry Leonard (1998) Genomic organization and partial duplication of the human a7 neuronal nicotinic acetylcholine receptor gene. Genomics 52:173-185.2. Sherry Leonard, Judith Gault, Theodore Moore, Jan Hopkins, Misi Robinson, Ann Olincy, Lawrence E. Adler, C. Robert Cloninger, Charles A. Kaufmann, Ming T. Tsuang, Stephen V. Faraone, Dolores Malaspina, Dragan M. Svrakic, and Robert Freedman. (1998) Further Investigation of a chromosome 15 locus in schizophrenia: Analysis of affected sibpairs from the NIMH Genetics Initiative. Am. J. Med. Gen.- Neuropsychiatric Genetics 81:308-312.
3. Leonard, S., Breese, C., Adams, C., Benhammou, K., Gault, J., Stevens, K., Lee, M., Adler, L., Olincy, A., Ross, R., and Freedman, R. (2000) Smoking and schizophrenia: abnormal nicotinic receptor expression. Eur. J. Pharm. 393: 237-242.
4. Weiland, S., Bertrand, D., Leonard, S. Neuronal nicotinic acetylcholine receptors: from the gene to the disease. (2000) Behav. Brain Res. 113:43-56.
5. Breese, C.R., Lee, M.J., Adams, C.E., Sullivan, B., Logel, J., Gillen, K.M., Marks, M.J., Collins, A.C., Leonard, S. (2000) Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology. 23:351-364
6. Benhammou, K., Lee, M., Strook, M.A., Sullivan, B., Logel, J., Raschen, K., Gotti, C., and Leonard, S. (2000). [3H] Nicotine binding in peripheral blood cells of smokers is correlated with the number of cigarettes smoked per day. Neuropharmacology 39:2818-2829.
7. Freedman, R., Leonard, S., Gault, J.M., and Hopkins, J. (2001) Linkage disequilibrium for schizophrenia at the chromosome 15q14 locus of the a7-nicotinic acetylcholine receptor subunit gene (CHRNA7). Am. J. Med. Gen. 105:20-22.
8. Freedman,R. and Leonard,S. (2001). Genetic linkage to schizophrenia at chromosome 15q14. American Journal of Medical Genetics 105, 655-657.
9. Leonard, S., Adler, L.E., Benhammou, K., Berger, R., Breese, C.R., Drebing, C., Gault, J., Lee, M.J., Logel, J., Olincy, A., Ross, R.G., Stevens, K., Sullivan, B., Vianzon, R., Vernich, D.E., Waldo, M., Walton, K., and Freedman, R. (2001). Smoking and mental illness. Pharmacol. Biochem. Behav. 70:561-570.
10. Freedman, R., Adler, L.E., Olincy, A., Waldo, M.C., Ross, R.G., Stevens, K.E., Leonard, S. (2002) Input dysfunction, schizotypy, and genetic models of schizophrenia. Schiz. Res. 54:25-32.
11. Leonard,S., Gault,J., Hopkins,J., Logel,J., Drebing,C., Vianzon,R., Short,M., Berger,R., Robinson,M., Freedman,R. (2002) Promoter variants in the nAChR? 7 gene are associated with schizophrenia and with a sensory processing deficit found in the disease. Archives of General Psychiatry 59:1085-1096.
12. Ross RG, Olincy A, Mikulich SK, Radant AD, Harris JG, Waldo M, Compagnon N, Heinlein S, Leonard S, Zerbe GO, Adler L, Freedman R. (2002) Admixture analysis of smooth pursuit eye movements in probands with schizophrenia and their relatives suggests gain and leading saccades are potential endophenotypes. Psychophysiology 39:809-819.
13. Gault,J., Hopkins,J., Berger,R., Drebing,C., Logel,J., Walton,K., Short,M., Vianzon,R., Olincy,A., Ross,R.G., Adler,L.E., Freedman,R., Leonard,S. (2003) Comparison of Polymorphism in the ?7 Nicotinic Receptor Gene Cluster in Schizophrenic and Control Subjects. Am. J. Med. Gen. 123B (1): 39-49.
14. Leonard, S. (2003) Consequences of low levels of nicotinic receptor gene expression in schizophrenia for drug development. Drug Dev. Res. 60:127-136.
15. Freedman, R., Leonard, S. Waldo, M., Gault, J., Adler, L. Olincy, A. (2004) Characterization of Allelic Variants at Chromosome 15q14 in Schizophrenia. Genes, Brain, Behav. (In Press).
16. Peng, J-H., Fryer, J.D., Hurst, R.S., Schroeder, K.M., George, A.A., Morrissy, S., Groppi, V.E., Leonard, S.S., Lukas, R.J. High-affinity epibatidine binding of functional, human ?7-nicotinic acetylcholine receptors heterologously expressed de Novo in Human Sh-EP1 Cells. J. P. E. T. in press.
POSTDOCTORAL RESEARCH TRAINING PROGRAM IN DEVELOPMENTAL PSYCHOBIOLOGYDepartment of Psychiatry
University of Colorado Health Sciences Center
Denver, CO 80262For additional Information E-mail:
Martin.Reite@UCHSC.edu
If you have any comments or suggestions, feel free to E-mail:
Linda.Greco-Sanders@UCHSC.edu
