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The Journal of Neuroscience, May 17, 2006, 26(20):5277-5287; doi:10.1523/JNEUROSCI.4602-05.2006

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Cellular/Molecular
Combined Application of Behavior Genetics and Microarray Analysis to Identify Regional Expression Themes and Gene–Behavior Associations

Noah E. Letwin,^1,2 Neri Kafkafi,³ Yoav Benjamini,⁴ Cheryl Mayo,³ Bryan C. Frank,¹ Troung Luu,¹ Norman H. Lee,^1,2 and Greg I. Elmer³

¹Department of Functional Genomics, The Institute for Genomic Research, Rockville, Maryland 20850, ²Department of Pharmacology, The George Washington University, Washington, DC 20037, ³Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21228, and ⁴Department of Statistics and Operation Research, The Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel

Correspondence should be addressed to either of the following: Norman H. Lee, The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, MD 20850, Email: nhlee{at}tigr.org or Greg I. Elmer, Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, gelmer{at}mprc.umaryland.edu

In this report we link candidate genes to complex behavioral phenotypes by using a behavior genetics approach. Gene expression signatures were generated for the prefrontal cortex, ventral striatum, temporal lobe, periaqueductal gray, and cerebellum in eight inbred strains from priority group A of the Mouse Phenome Project. Bioinformatic analysis of regionally enriched genes that were conserved across all strains revealed both functional and structural specialization of particular brain regions. For example, genes encoding proteins with demonstrated anti-apoptotic function were over-represented in the cerebellum, whereas genes coding for proteins associated with learning and memory were enriched in the ventral striatum, as defined by the Expression Analysis Systematic Explorer (EASE) application. Association of regional gene expression with behavioral phenotypes was exploited to identify candidate behavioral genes. Phenotypes that were investigated included anxiety, drug-naive and ethanol-induced distance traveled across a grid floor, and seizure susceptibility. Several genes within the glutamatergic signaling pathway (i.e., NMDA/glutamate receptor subunit 2C, calmodulin, solute carrier family 1 member 2, and glutamine synthetase) were identified in a phenotype-dependent and region-specific manner. In addition to supporting evidence in the literature, many of the genes that were identified could be mapped in silico to surrogate behavior-related quantitative trait loci. The approaches and data set described herein serve as a valuable resource to investigate the genetic underpinning of complex behaviors.

Key words: mouse; seizure; phenotype; glutamate receptor; transcriptome; neuroanatomy

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Received Oct. 27, 2005; revised March 22, 2006; accepted March 23, 2006.

Correspondence should be addressed to either of the following: Norman H. Lee, The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, MD 20850, Email: nhlee{at}tigr.org or Greg I. Elmer, Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, gelmer{at}mprc.umaryland.edu

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