LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease.

Several psychiatric diseases, including schizophrenia, are thought to have a developmental aetiology, but to date no clear link has been made between psychiatric disease and a specific developmental process. LPA(1) is a G(i)-coupled seven transmembrane receptor with high affinity for lysophosphatidic acid. Although LPA(1) is expressed in several peripheral tissues, in the nervous system it shows relatively restricted temporal expression to neuroepithelia during CNS development and to myelinating glia in the adult. We report the detailed neurological and behavioural analysis of mice homozygous for a targeted deletion at the lpa(1) locus. Our observations reveal a marked deficit in prepulse inhibition, widespread changes in the levels and turnover of the neurotransmitter 5-HT, a brain region-specific alteration in levels of amino acids, and a craniofacial dysmorphism in these mice. We suggest that the loss of LPA(1) receptor generates defects resembling those found in psychiatric disease.

A longitudinal magnetic resonance imaging (MRI) study of differences in abdominal fat distribution between normal mice, and lean overexpressers of mitochondrial uncoupling protein-3 (UCP-3).

AIM: To characterize evolution and distribution of abdominal adipose fat between 6 and 18 weeks of age in an animal model of energy consumption based on mice overexpressing the mitochondrial uncoupler protein 3 (UCP-3). METHODS: T2-weighted multislice MRI was performed six times during the 12 week study; visceral, subcutaneous and intermuscular fat depots were quantified. RESULTS: The overexpressor (UCP-3tg) mice consistently have less subcutaneous, visceral, interskeletal muscle and total fat throughout the experiment. Mean (standard error) volumes (ml) of the three distinct depots change between week 6 and week 18 as follows: wild type: subcutaneous 1.93 (0.28) to 6.18 (0.47), visceral 2.15 (0.34) to 6.37 (0.64), intermuscular 0.23 (0.04) to 0.53 (0.03); UCP-3tg: subcutaneous 1.47 (0.17) to 4.07 (0.57), visceral 1.18 (0.04) to 3.69 (0.59), intermuscular 0.23 (0.01) to 0.32 (0.04). Although they eat more (4.3 g compared with 3.4 g per day) the UCP-3tg's always weigh less than controls. In wild-type control animals, increases of all fat pools between week 6 and week 18 is highly significant, as it is for subcutaneous, visceral and total pools in the UCP-3tg animals. The UCP-3tg mice, however, show no significant absolute or relative increase in intermuscular fat; UCP-3 is predominantly overexpressed in skeletal muscle. CONCLUSION: MRI provides an excellent approach to comparative studies of fat distribution in animal models of energy expenditure such as the UCP-3tg mouse.

SHIRPA, a protocol for behavioral assessment: validation for longitudinal study of neurological dysfunction in mice.

Mouse models of neurological abnormalities are only valuable if accurately assessed. The three-stage SHIRPA procedure is used for the standardised assessment of mouse phenotype and has been reported in a high throughput experiment in which different mutants were ascertained at one age point using stage 1 of the protocol. In this study we have validated SHIRPA using a large cohort with one single mutation, 'legs at odd angles that causes neurological dysfunction. The cohort aged from 1 to 16 months during this study and this is the first longitudinal SHIRPA analysis.

C3H apoE(-/-) mice have less atherosclerosis than C57BL apoE(-/-) mice despite having a more atherogenic serum lipid profile.

Wild-type C57BL mice are known to be susceptible to diet-induced atherosclerosis, whilst C3H mice are resistant. We investigated the effect of these background strains on the hyperlipidaemia and atherosclerosis that develops in mice deficient in apolipoprotein E (apoE(-/-)). Male and female apoE(-/-) mice on C3H/HeNHsd (C3H) and C57BL/6J (C57) backgrounds were fed atherogenic Western diet for 12 weeks. Serum cholesterol and triglyceride concentrations were measured and atherosclerosis quantified in the aortic sinus. C3H apoE(-/-) mice fed normal diet had 1.5 2 fold higher serum cholesterol levels than C57 apoE(-/-) mice and 4-5 fold higher serum triglyceride concentrations. Feeding Western diet caused a 4-5 fold increase in serum cholesterol in all mice, but levels of triglyceride were either attenuated or were unaffected in C3H apoE(-/-) and C57 apoE(-/-) mice, respectively. C3H apoE(-/-) mice had approximately 2 fold higher serum cholesterol and 4 fold higher triglyceride concentrations than the C57 apoE(-/-) mice throughout the study. Serum triglyceride concentrations were 35-108% higher in male C3H apoE(-/-) than female C3H apoE(-/-) mice. Most of the lipids were present in the very low density lipoprotein (VLDL)/chylomicron fraction in both strains of mice whether they were fed normal or Western diet. Notwithstanding the lower plasma lipid concentrations, atherosclerotic lesion areas were more than 2-fold larger in C57 apoE(-/-) than in C3H apoE(-/-) mice (males 68 +/- 11 x 10(3) vs 30 +/- 6 x 10(3) females 102 +/- 12 x 10(3) vs 41 +/- 8 x 10(3) microm2. mean +/- SEM).

Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean.

Uncoupling protein-3 (UCP-3) is a recently identified member of the mitochondrial transporter superfamily that is expressed predominantly in skeletal muscle. However, its close relative UCP-1 is expressed exclusively in brown adipose tissue, a tissue whose main function is fat combustion and thermogenesis. Studies on the expression of UCP-3 in animals and humans in different physiological situations support a role for UCP-3 in energy balance and lipid metabolism. However, direct evidence for these roles is lacking. Here we describe the creation of transgenic mice that overexpress human UCP-3 in skeletal muscle. These mice are hyperphagic but weigh less than their wild-type littermates. Magnetic resonance imaging shows a striking reduction in adipose tissue mass. The mice also exhibit lower fasting plasma glucose and insulin levels and an increased glucose clearance rate. This provides evidence that skeletal muscle UCP-3 has the potential to influence metabolic rate and glucose homeostasis in the whole animal.

Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia.

The vanilloid receptor-1 (VR1) is a ligand-gated, non-selective cation channel expressed predominantly by sensory neurons. VR1 responds to noxious stimuli including capsaicin, the pungent component of chilli peppers, heat and extracellular acidification, and it is able to integrate simultaneous exposure to these stimuli. These findings and research linking capsaicin with nociceptive behaviours (that is, responses to painful stimuli in animals have led to VR1 being considered as important for pain sensation. Here we have disrupted the mouse VR1 gene using standard gene targeting techniques. Small diameter dorsal root ganglion neurons isolated from VR1-null mice lacked many of the capsaicin-, acid- and heat-gated responses that have been previously well characterized in small diameter dorsal root ganglion neurons from various species. Furthermore, although the VR1-null mice appeared normal in a wide range of behavioural tests, including responses to acute noxious thermal stimuli, their ability to develop carrageenan-induced thermal hyperalgesia was completely absent. We conclude that VR1 is required for inflammatory sensitization to noxious thermal stimuli but also that alternative mechanisms are sufficient for normal sensation of noxious heat.

Effect of probucol on serum lipids, atherosclerosis and toxicology in fat-fed LDL receptor deficient mice.

Although numerous transgenic mouse models for atherosclerosis have been developed recently, little is known about their response to hypolipidaemic or anti-atherosclerotic agents. We investigated the effect of the known hypocholesterolaemic and anti-atherosclerotic drug probucol on serum lipids, lipoproteins and atherosclerosis in fat-fed low density lipoprotein (LDL) receptor deficient mice. Probucol at doses of 0.2 and 1% in the diet which are similar to those used in the mouse by other investigators reduced serum cholesterol by 26 and 37%, respectively. Probucol also reduced serum triglyceride levels by 33 and 47% at doses of 0.2 and 1%, respectively. The decrease in serum cholesterol and triglycerides was mainly due to a decrease of these lipids in VLDL and or chylomicrons. Despite these potentially beneficial changes in serum lipids atherosclerotic lesion areas in the aortic root were unchanged in the probucol treated mice. After 12 weeks treatment most of the mice receiving probucol had swollen feet and tails due to oedema. Histological examination of the base of the hearts from the probucol treated mice revealed lipid droplets within the reticuloendothelial and other interstitial cells. There was also an interstitial subacute inflammatory cell infiltration associated with the lipid deposition. The oedema induced by probucol could be the result of cardiac insufficiency due to interstitial lipidosis and inflammation in the base of the heart together with the extensive atherosclerotic lesions in the aortic sinus.