Department of Psychiatry

Postdoctoral Research Training in
Developmental Psychobiology

Sherry Leonard, Ph.D.

Dr. 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.

Contact Dr. Leonard:
Sherry.Leonard@ucdenver.edu
(303) 724-4426