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Discrete Neuron Transcription Patterns in the Entorhinal Cortex

Scott E. Hemby, PhD; Stephen D. Ginsberg, PhD; Brian Brunk, PhD; Steven E. Arnold, MD; John Q. Trojanowski, MD, PhD; James H. Eberwine, PhD

Arch Gen Psychiatry. 2002;59:631-640.

Background  Several lines of evidence indicate the altered function of the temporal lobe, including the hippocampus and entorhinal cortex (EC), is associated with schizophrenia. We used single-cell gene expression technologies to assess coordinate changes in the expression of multiple genes, including neuronal signaling and synaptic-related markers in EC layer II stellate neurons.

Methods  We used a single-neuron microdissection technique coupled with linear antisense RNA amplification and high density/candidate gene arrays to assess coordinate changes in gene expression. The expression and relative abundance of more than 18 000 messenger RNAs were assessed from EC layer II stellate neurons from postmortem samples of schizophrenic and age-matched control brains. Results of this initial screen were used to perform a more specific secondary messenger RNA screen for each subject.

Results  Data disclosed marked differences in expression of various G-protein–coupled receptor-signaling transcripts, glutamate receptor subunits, synaptic proteins, and other transcripts. Results of secondary screening showed significant decreases in levels of G-protein subunit i1, glutamate receptor 3, N-methyl-D-aspartate receptor 1, synaptophysin, and sensory nerve action potentials 23 and 25 in the stellate neurons of schizophrenic patients. We observed down-regulation of phospholemman (a phosphoprotein associated with anion channel formation) messenger RNA and protein levels in layer II/III stellate neurons in the population with schizophrenia.

Conclusions  These results provide a preliminary expression profile of schizophrenia in defined neuronal populations. Understanding the coordinated involvement of multiple genes in human disease provides insight into the molecular basis of the disease and offers new targets for pharmacotherapeutic intervention.

From the Departments of Pharmacology and Psychiatry and Behavioral Sciences, Yerkes Regional Primate Research Center, Neuroscience Division, Emory University School of Medicine, Atlanta, Ga (Dr Hemby); the Dementia Research Program, Department of Psychiatry, Nathan Kline Institute, New York University School of Medicine, Orangeburg (Dr Ginsberg); and the Center for Bioinformatics (Dr Brunk) and the Departments of Psychiatry (Drs Arnold and Eberwine), Neurology (Drs Arnold and Eberwine), Pharmacology (Dr Eberwine), and Pathology and Laboratory Medicine (Dr Trojanowski), University of Pennsylvania School of Medicine, Philadelphia. Dr Hemby is a consultant for Solvay Pharmaceuticals, Utrecht, the Netherlands. Dr Eberwine is on the Scientific Advisory Board of Incyte Pharmaceuticals, Sunnyvale, Calif, which owns Genome Systems. Drs Eberwine and Trojanowski are Founding Scientists, consultants and stockholders for Layton BioScience, Inc, Sunnyvale, which has licensed the aRNA amplification and in situ transcription methods.

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