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Diabetes insipidus and, partially, low anxiety‐related behaviour are linked to a SNP‐associated vasopressin deficit in LAB mice

2007; Wiley; Volume: 26; Issue: 10 Linguagem: Inglês

10.1111/j.1460-9568.2007.05917.x

1460-9568

Melanie Keßler, Chris Murgatroyd, Mirjam Bunck, Ludwig Czibere, Elisabeth Frank, W. Jacob, Charlotte Horvath, Patrik Muigg, Herta Flor, Nicolas Singewald, Dietmar Spengler, Rainer Landgraf,

Stress Responses and Cortisol

Following secretion from the posterior pituitary, the neuropeptide vasopressin (AVP) stimulates the kidney to retain water, and when released centrally it can contribute to anxiety- and depression-like behaviours. We hypothesized that CD1 mice bred for low trait anxiety (LAB) suffer from a deficit in AVP. Both osmotically stimulated peripheral secretion and intra-paraventricular nucleus (PVN) release of AVP were found decreased in LAB animals compared with normal anxiety (NAB) or high anxiety (HAB) controls. Consequently, in addition to their extreme non-anxiety, LAB mice showed signs of central diabetes insipidus (cDI), including increased fluid intake and reduced urine osmolality, as well as a pathological increase in plasma osmolality upon water deprivation. These cDI symptoms were attenuated by administration of a selective AVP V2 receptor agonist. A single nucleotide polymorphism (SNP) in exon 1 (C(+40)T) of the Avp gene of LAB animals causes an amino acid substitution in the signal peptide of the AVP precursor, and is likely to impair processing and trafficking of the precursor, as suggested by reduced axonal transport of AVP from the hypothalamic PVN, finally contributing to cDI symptoms and low trait anxiety. In an F2 panel, this SNP co-segregated with fluid intake and showed a partial contribution to low anxiety-related behaviour, indicated by its co-segregation with time spent on the open arms of the elevated plus-maze in a subset of F2 mice. Thus, the SNP-associated deficit in plasma and central AVP contributes to signs of cDI and, at least partially, to low trait anxiety, both features being typical of LAB animals.