HMGP - Sherry Leonard, Ph.D.

Sherry Leonard, Ph.D.
Genetic determinants of schizophrenia and nicotine addiction

Departments of Pharmacology and Psychiatry and the Veterans Administration
Box C-268-71
University of Colorado Denver
4200 East 9th Avenue
Denver, CO 80262

Research in Dr. Leonard's laboratory focuses on the molecular neurobiology of neuronal nicotinic acetylcholine receptors in both nicotine addiction and 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 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 1/2 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 disease can often simplify both the neurobiology and 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 olignucleotides, 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 both low and high affinity nicotinic receptors is decreased in the hippocampus of schizophrenics, compared to controls. We have cloned both a human cDNA and genomic sequence for the a7 gene. A simple sequence repeat, isolated from the genomic clone, was recently used to show linkage of the gating deficit in schizophrenia to chromosome 15 (15gl3-14), the locus of the a7 nicotinic receptor gene. We have discovered the a7 gene to be partially duplicated. The duplication of exons 5-10 also reside on chromosome 15 and are expressed with novel exons as both mRNA and protein. This is, thus, a new gene with nicotinic receptor homology. We are presently involved in an extensive effort to find mutations in the a7 gene cluster, which could account for the failure of filter sensory input in schizophrenics. The duplicated a7 gene is missing in 5 schizophrenic subjects.

In other work ongoing in the laboratory, regional expression and function of the a7 nicotinic receptor, as well as other nicotinic subunits, is being examined in postmortem brain tissue of controls and subjects who were mentally ill in life. Nicotinic receptors are increased in the brains of normal smokers, and the number of receptors is directly correlated with the number of cigarettes smoked per day. However, in schizophrenics, this regulatory mechanism appears to be defective as there is no increase in receptor number in the mentally ill smokers. We are currently investigating several possibilities for this difference, including a constitutively lower level of receptors and/or aberrant regulation.

Publications

Breese, C.R., Marks, M., Logel, J., Adams, C., Sullivan, B., Collins, A.C., Leonard, S. (1997) Effect of smoking history on [3H]-nicotine binding in human postmortem brain. J. Pharm. Exper. Therapeut. 282:7-13.

Breese, C., Adams, C., Logel, J., Drebing, C., Rollins, Y., Barnhart, M., Sullivan, B., Demasters, B.K., Freedman, R., and Leonard, S. (1997) Comparison of the regional expression of nicotinic acetylcholine receptor (7 mRNA and [125 I]-(-bungarotoxin binding in human postmortem brain. J. Comp. Neurol. 387:385-398.

Leonard, S., Gault, J., Adams, C., Breese, C.R., Rollins, Y., Adler, L.E., Olincy, A., and Freedman, R. (1998) Nicotinic receptors, smoking and schizophrenia. Restorative Neurol. Neurosci. 12:195-201.

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.

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 (7 neuronal nicotinic acetylcholine receptor gene. Genomics 52:173-185.

Sherry Leonard, Lawrence E. Adler, Ann Olincy, Charles R. Breese, Judith Gault, Randal G. Ross, Michael Lee, Ellen Cawthra, Herbert T. Nagamoto, and Robert Freedman. "The Role of Nicotine in Psychopathology", in Neuronal Nicotinic Receptors: Pharmacology and Therapeutic Opportunities, Editors S.P. Arneric and J.D. Brioni., John Wiley & Sons, New York. pp. 307-321, 1998.

Freedman, R., Adler, L.E. and Leonard, S. (1999) Alternative phenotypes for the complex genetics of schizophrenics. Biol. Psych. 45:551-558.

Peng, J.-H., Lucero, L., Fryer, J., Herl, J., Leonard, S.S., Lukas, R.J. (1999) Inducible, heterologous expression of human (7-nicotinic acetylcholine receptors in a native nicotinic receptor-null human clonal line. Brain Res. 825:172-179.

Olincy, A., Leonard, S., Young, D.A., Sullivan, B., and Freedman, R. (1999). Decreased bombesin peptide response to cigarette smoking in schizophrenia. Neuropsychopharmacology 20:52-59.

Craddock, N., Lendon, C., Cichon, S., Culverhouse, R., Detera-Wadleigh, S., Devon, R., Faraone, S., Foroud, T., Gejman, P., Leonard, S., McInnis, M., Owen, M.J., Riley, B., Armstrong, C., Barden, N., van Broeckhoven, C., Ewald, H., Folstein, S., Gerhard, D., Goldman, D., Gurling, H., Kelsoe, J., Levinson, D., Muir, W., Philippe, A., et al. (1999).

Chromosome workshop: chromosomes 11, 14, and 15. American Journal of Medical Genetics 88(3):244-254.

Peng, J.-H., Lucero, L., Fryer, J., Herl, J., Leonard, S.S., and Lukas, R.J. (1999). Inducible, heterologous expression of human ?7-nicotinic acetylcholine receptors in a native nicotinic receptor-null human clonal line. Brain Res. 825:172-179.

Morton, C.C., Christian, S.L., Donlon, T.A., Driscoll, D.J., Fink, J.K., Gabriel, J.M., Gotway, G., Greally, J.M., Hitchins, M.P., Howard, H.C., Ji, Y., Leonard, S., Lerner, T., Magenis, E., Malcolm, S., Ohta, T., Rainier, S., Rees, M., Riley, B., Robinson, W.P., Saitoh, S., Schultz, R., Sell, S., Sharp, J.D., Nicholls, R.D., et al. (1999). Report of the fourth international workshop on human chromosome 15 mapping. Cytogen. Cell Gen. 84:12-21.

Waldo, M.C., Adler, L.E., Leonard, S., Olincy, A., Ross, R.G., Harris, J.G., and Freedman, R. (2000). Familial transmission of risk factors in the first-degree relatives of schizophrenic people. Biol. Psych. 47:231-239.

Yao, J.K., Leonard, S., and Reddy, R.D. (2000). Membrane phospholipid abnormalities in postmortem brains from schizophrenic patients. Schiz. Res. 42:7-17.

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.

Stitzel, J.A., Leonard, S.S., and Collins A.C. (2000). Genetic regulation of nicotine-related behaviors and brain nicotinic receptors. In: Neuronal Nicotinic Receptors. F. Clementi, C. Gotti, and D. Fornasari (eds), Springer-Verlag (Berlin, Heidelberg, New York), pp. 563-585.

Weiland, S., Bertrand, D., and Leonard, S. (2000). Neuronal nicotinic acetylcholine receptors: from the gene to the disease. Behavioral Brain Research 113:43-56.

Breese, C.R., Lee, M.J., Adams, C.E., Sullivan, B., Logel, J., Gillen, K.M., Marks, M.J., Collins, A.C., and Leonard, S. (2000). Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology 23:351-364.

Freedman, R., Adams, C.E., Adler, L.E., Bickford, P.C., Gault, J., Harris, J.G., Nagamoto, H.T., Olincy, A., Ross, R.G., Stevens, K.E., Waldo, M., and Leonard, S. (2000). Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia. J. Med. Gen. (Semin. Med. Genet.) 97:58-64.

Freedman, R., Adams, C.E., Leonard, S. (2000) The alpha 7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia. J. Chem. Neuroanat. 20: 299-306.

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.

McCallum, S.E., Caggiula, A.R., Booth, S., Breese, C.R., Lee, M.J., Donny, E.C., Leonard, S., and Sved, A.F. (2000). Mecamylamine prevents tolerance but enhances whole brain [3H] epibatidine binding in response to repeated nicotine administration in rats. Psychopharmacology 150:1-8.

Buervenich, S., Carmine, A., Arvidsson, M., Xiang, F., Zhang, Z., Sydow, O., Jönsson, E.G., Sedvall, G.C., Leonard, S., Ross, R.G., Freedman, R., Chowdari, K.V., Nimgaonkar, V.L., Perlmann, T., Anvret, M., and Olson, L. (2000). NURR1 mutations in cases of schizophrenia and manic depressive disorder. Am. J. Med. Gen., Neuropsych. Gen. 96:808-813.

Lee, M.J., Breese, C.R., and Leonard, S. (2001). The effect of nicotine and haloperidol co-treatment on nicotinic receptor levels in the rat brain. Mol. Brain Res. 86:115-124.

Freedman, R., Leonard, S., Gault, J.M., Hopkins, J., Cloninger, C.R., Kaufmann, C.A., Tsuang, M.T., Faraone, S.V., Malaspina, D., Svrakic, D.M., Sanders, A., and Gejman, P. (2001). Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the ?7-nicotinic acetylcholine receptor subunit gene (CHRNA7). Am. J. Med. Gen., Neuropsych. Gen. 105:20-22.

Freedman, R., Leonard, S., Olincy, A., Kaufmann, C.A., Malaspina, D., Cloninger, R., Svrakic, D., Faraone, S.V., and Tsuang, M.T. (2001). Evidence for the multigenic inheritance of schizophrenia. Am. J. Med. Gen. (Neuropsych. Gen) 105:794-800.

Leonard, S. and Bertrand, D. (2001). Neuronal nicotinic receptors: from structure to function. Nicotine & Tobacco Research 3:203-223.

Freedman,R. and Leonard,S. (2001). Genetic linkage to schizophrenia at chromosome 15q14. American Journal of Medical Genetics 105, 655-657.

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.

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.

Leonard, S. and Giordano, L. Are differential behavioral responses to smoking and smoking cessation in schizophrenia related to nicotinic receptor levels? (2002) Neuropsychopharmacol. 27:1082-1083.

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.

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.

Leonard, S. and Freedman, R. Recombination in a schizophrenic probands fails to exclude CHRNA7 at chromosome 15q14. (2003) Mol. Psych. 8:145-146.

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.

Freedman R. Olincy A. Ross RG. Waldo MC. Stevens KE. Adler LE. Leonard S. The genetics of sensory gating deficits in schizophrenia. (2004) Current Psychiatry Reports. 5(2):155-61.

Leonard, S. (2003) Consequences of low levels of nicotinic receptor gene expression in schizophrenia for drug development. Drug Dev. Res. 60:127-136.

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 in the native receptor-null SH-EP1 human epithelial cell line. In Press, JPET.

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).

Yao, J.K., Leonard, S., and Reddy, R.D. Increased nitric oxide radicals in postmortem brain from patients with schizophrenia. In press, Schizophrenia Bulletin.