Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion.

Perturbation of Disrupted-In-Schizophrenia-1 (DISC1) and D-serine/NMDA receptor hypofunction have both been implicated in the pathophysiology of schizophrenia and other psychiatric disorders. In the present study, we demonstrate that these two pathways intersect with behavioral consequences. DISC1 binds to and stabilizes serine racemase (SR), the enzyme that generates D-serine, an endogenous co-agonist of the NMDA receptor. Mutant DISC1 fails to bind to SR, facilitating ubiquitination and degradation of SR and a decrease in D-serine production. To elucidate DISC1-SR interactions in vivo, we generated a mouse model of selective and inducible expression of mutant DISC1 in astrocytes, the main source of D-serine in the brain. Expression of mutant DISC1 downregulates endogenous DISC1 and decreases protein but not mRNA levels of SR, resulting in diminished production of D-serine. In contrast, mutant DISC1 does not alter levels of ALDH1L1, connexins, GLT-1 or binding partners of DISC1 and SR, LIS1 or PICK1. Adult male and female mice with lifelong expression of mutant DISC1 exhibit behavioral abnormalities consistent with hypofunction of NMDA neurotransmission. Specifically, mutant mice display greater responses to an NMDA antagonist, MK-801, in open field and pre-pulse inhibition of the acoustic startle tests and are significantly more sensitive to the ameliorative effects of D-serine. These findings support a model wherein mutant DISC1 leads to SR degradation via dominant negative effects, resulting in D-serine deficiency that diminishes NMDA neurotransmission thus linking DISC1 and NMDA pathophysiological mechanisms in mental illness.

[Changes in Galphaq/11 mediated signal transduction pathway in the aorta of two kidney one clip hypertensive rats].

The objective of this study was to investigate the role of signal transduction pathway mediated by Galphaq/11 of the aorta in blood pressure regulation during the development of two-kidney one clip (2K1C) Glodblatt hypertension in the rat. Levels of Galphaq/11-subunit and extracellular signal regulated kinase 1/2 (ERK1/2) of the aorta were measured by Western blot analysis at week 1, 2, 4 or 8 after operation. Phospholipase C (PLC) activity of the aorta was measured by using (3)H phosphatidylinostol (4,5) bisphosphate as a substrate. Both systolic and diastolic blood pressure increased markedly in 2K1C rats at week 2, 4 or 8, whereas, the increase in Galphaq/11 and ERK1/2 expression of the aorta began at week 1 after operation (increased by 57.53% and 40.16%, respectively), and maintained at a high level during week 2 8 compared with time matched controls (P<0.01). PLC activities in the aorta were also increased significantly in 2K1C groups at week 4 and 8 compared with the time matched controls (P<0.05). The results indicate that Galphaq/11-mediated signal transduction pathway of the aorta is activated in 2K1C hypertension, and may contribute to the initiation and maintenance of renal hypertension.

[The effect of lycium barbarum polysaccharide on vascular tension in two-kidney, one clip model of hypertension].

In the present study, the effects of lycium barbarum polysaccharide (LBP) on endothelial function in the two-kidney, one clip model of hypertension were observed. The results showed that the increase of blood pressure in hypertension rats (HR) could be prevented significantly by treatment with 10% LBP. In isolated aortic rings of LBP-treated rats, the contraction of phenylephrine (PE) was reduced as compared with HR rats. Removal of the endothelium abolished the difference of PE-induced vasoconstriction among groups. In vitro incubation of aortic rings from LBP-treated rats with methyl blue (MB) or N-nitro-L-arginine methyl ester (L-NAME) increased the magnitude of PE-induced contraction. Meanwhile the response to acetylcholine (ACh) was significantly increased in LBP-treated rats, but the response to nitroprusside had no significant difference among groups. Pretreatment with L-arginine partially restored ACh-induced relaxation in RH rats, but no effect in LBP-treated rats. These results suggested that the role of LBP in decreasing vasoconstriction to PE may be mediated by increase of the effects or/and production of endothelium-derived relaxation factor (EDRF). LBP increased formation of EDRF may be related to increase the substrate of EDRF.

[The dynamic changes of NOSmRNA in endothelial cells of aortae and pulmonary arteries in rats under tail suspension].

Objective. Through the observations of dynamic changes of eNOSmRNA and iNOSmRNA in arterial endothelial cells of systematic circulation and pulmonary circulation under simulated weightlessness, to collect some data for studies of the adaptive mechanisms of local regulation in arterial systems. Method. Wistar rats were -30 degrees tail suspended to simulate the effects of weightlessness. The rats were randomly divided into three groups: control group (CON), 7-day tail suspension group (TS7) and 14-day tail suspension group (TS14). Changes of NOSmRNA expresses in endothelial cells of the thoracic aortae and pulmonary arteries were observed with in situ hybridization technique. Result. The eNOSmRNA and iNOSmRNA of thoracic aortic and pulmonary arterial endothelial cells in TS7 rats increased very significantly. The eNOSmRNA of thoracic aortic endothelial cells from TS14 rats returned to control level, but remained very significantly increased in pulmonary arteries. The iNOSmRNA in pulmonary arterial endothelial cells from TS14 rats decreased very significantly, but that in thoracic aortae returned to the control level. Conclusion. The responses of eNOSmRNA and iNOSmRNA in arterial endothelial cells of systematic circulation to tail suspension were similar, but they were different in pulmonary arterial endothelial cells, which might be due to the difference in the peak course of the shift of fluid from lower body entering the pulmonary or systematic circulation during initial period of simulated weightlessness. It could be a kind of important sign of depressed local regulative function under simulated weightlessness and might contribute to orthostatic intolerance after simulated weightlessness.

Comparison of outcomes by modality for critically ill patients requiring renal replacement therapy: a single-centre cohort study adjusting for time-varying illness severity and modality exposure.

Prolonged intermittent renal replacement therapy (PIRRT) is a recently defined acute modality for critically ill patients, and in theory combines the superior detoxification and haemodynamic stability of continuous renal replacement therapy (CRRT) with the operational convenience and low cost of intermittent haemodialysis (iHD). We performed a retrospective cohort study for all critically ill adults treated with renal replacement therapy at our centre in Auckland, New Zealand from 1 January 2002 to 31 December 2008. The exposure of interest was modality (PIRRT, CRRT, iHD). Primary and secondary outcomes were patient mortality determined at hospital discharge and 90 days post renal replacement therapy inception, respectively. Co-variates included co-morbidity and baseline illness severity measured by Acute Physiology and Chronic Health Evaluation IV and Sepsis-Related Organ Failure Assessment (SOFA) and time-varying illness severity measured by daily SOFA scores. We used Marginal Structural Modelling to estimate mortality risk adjusting for both time-varying illness severity and modality exposure. A total of 146 patients with 633 treatment-days had sufficient data for modelling. With PIRRT as the reference, the adjusted hazard ratios for patient hospital mortality were 1.31 (0.60 to 2.90) for CRRT and 1.22 (0.21 to 2.29) for iHD. Corresponding estimates for mortality at 90 days were 0.96 (0.39 to 2.36) and 2.22 (0.49 to 10.11), respectively, reflecting the poorer longer-term prognosis of patients still on iHD at hospital discharge with delayed or non-recovery of acute kidney injury. Our study supports the recent increased use of PIRRT, which within limits can be regarded as safe and effective.