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

Abstract

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.

TMEM132D, a new candidate for anxiety phenotypes: evidence from human and mouse studies

“…Using an established animal model of extremes in the genetic predisposition to anxiety, 10,11,32 we could show that Tmem132d mRNA expression in the cingulate cortex is positively correlated with anxiety-related behavior. This observation was consistent in microarray and real-time quantitative reverse transcription PCR experiments as well as in male and female HAB, CD1 and LAB animals, suggesting a gender-independent relationship of Tmem132d with anxiety-related behavior ( Figure 5).…”

“…Animals for the following studies were inbred high (HAB) and low (LAB) anxiety-related behavior mice [10][11][12] or unselected outbred CD1 controls (Charles River Laboratories, Sulzfeld, Germany). All mice were tested for parameters indicative of anxietyrelated and depression-like behaviors as well as locomotor activity on the elevated plus-maze (EPM), in the tail-suspension test and in the open field.…”

“…10,11,32 Selection criterion was the EPM, which is known to model elements of PD. 33,34 Both HAB and LAB lines were described to respond to the panicogenic drug FG-7142 with an increase in Fos expression in the cingulate cortex.…”

“…Furthermore, to test for complementary inter-species effects, the clinical data were supported and extended by expression and association analyses in a mouse model of extremes in trait anxiety. [10][11][12] …”

Proteomic-based genotyping in a mouse model of trait anxiety exposes disease-relevant pathways

“…In the parental generation, the two polymorphisms located in the coding sequence of Enoph1 display opposite homozygosity in HABs (GG and CC) vs LABs (AA and TT). A total of 514 F2 offspring of a HABxLAB intercross (F1) progeny were phenotyped (anxiety-related behavior: EPM; locomotor activity: EPM and open field; depression-like behavior: tail-suspension test; for a more detailed description of behavioral tests see Krö mer et al 2 ) and genotyped at these two loci on the basis of DNA isolated from tail tips as described by Keler et al 6 Genotyping was performed using the manufacturer's protocol and genotypes were calculated using the BeadStudio software 3.1.0.0 and the Genotyping Module 3.1.12 (Illumina). Twenty-four samples were tested repeatedly, assuring data quality and reproducibility.…”