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The Journal of Neuroscience, September 1, 2004, 24(35):7762-7770; doi:10.1523/JNEUROSCI.1614-04.2004

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Neurobiology of Disease
Impaired Repression at a Vasopressin Promoter Polymorphism Underlies Overexpression of Vasopressin in a Rat Model of Trait Anxiety

Chris Murgatroyd,¹ Alexandra Wigger,¹ Elisabeth Frank,¹ Nicolas Singewald,² Mirjam Bunck,¹ Florian Holsboer,¹ Rainer Landgraf,¹ and Dietmar Spengler¹

¹Max-Planck-Institute of Psychiatry, 80804 Munich, Germany, and ²Department of Pharmacology and Toxicology, University of Innsbruck, A-6020 Innsbruck, Austria

Two inbred rat lines have been developed that show either high (HAB) or low (LAB) anxiety-related behavior. The behavioral phenotype correlates with arginine vasopressin (AVP) expression at the level of the hypothalamic paraventricular nucleus (PVN), but not supraoptic nucleus, with HAB animals overexpressing the neuropeptide in both magnocellular and parvocellular subdivisions of the PVN. We detected a number of single nucleotide polymorphisms (SNPs) in the AVP locus that differ between the HAB and LAB animals, two of which were embedded in cis-regulatory elements. The HAB-specific allele of the AVP gene promoter occurs in 1.5% of outbred Wistar rats and is more transcriptionally active in vivo, as revealed by allele-specific transcription studies in cross-mated HAB/LAB F1 animals. Interestingly, one specific SNP [A(-1276)G] conferred reduced binding of the transcriptional repressor CArG binding factor A (CBF-A) in the HAB allele, the consequent differential regulation of the AVP promoter resulting in an overexpression of AVP in vitro and in vivo. Furthermore, CBF-A is highly coexpressed in AVP-containing neurons of the PVN supporting an important role for regulation of AVP gene expression in vivo. Taken together, our results demonstrate a role for an AVP gene polymorphism and CBF-A in elevated AVP expression in the PVN of HAB rats likely to contribute to their behavioral and neuroendocrine phenotype.

Key words: anxiety; depression; common variant/common disease hypothesis; arginine vasopressin; hypothalamic-pituitary-adrenal axis; CBF-A

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Received March 26, 2004; revised July 22, 2004; accepted July 22, 2004.

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