Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment

In humans, phencyclidine (PCP), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reproduces a schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Thus, the glutamatergic neuronal dysfunction hypothesis is one of the main explanatory hypotheses and PCP-treated animals have been utilized as an animal model of schizophrenia. The adult rodents treated with PCP repeatedly exhibit hyperlocomotion as an index of positive symptoms, a social behavioral deficit in a social interaction test and enhanced immobility in a forced swimming test as indices of negative symptoms. They also show a sensorimotor gating deficits and cognitive dysfunctions in several learning and memory tests. Some of these behavioral changes endure after withdrawal from repeated PCP treatment. Furthermore, repeated PCP treatment induces some neurochemical and neuroanatomical changes. On the other hand, the exposure to viral or environmental insult in the second trimester of pregnancy increases the probability of subsequently developing schizophrenia as an adult. NMDA receptor has been implicated in controlling the structure and plasticity of developing brain circuitry. Based on neurodevelopment hypothesis of schizophrenia, schizophrenia model rats treated with PCP at the perinatal stage is developed. Perinatal PCP treatment impairs neuronal development and induces long-lasting schizophrenia-like behaviors in adult period. Many findings suggest that these PCP animal models would be useful for evaluating novel therapeutic candidates and for confirming pathological mechanisms of schizophrenia.     

Loureirin C and Xanthoceraside Attenuate Depression-Like Behaviors and Expression of Interleukin-17 in the Prefrontal Cortex Induced by Chronic Unpredictable Mild Stress in Mice

Neurochemical Research - Major depressive disorder (MDD) is the most prevalent and serious psychiatric disease involving inflammation. Loureirin C and Xanthoceraside are extracts of dragon’s...     

Beta2-microglobulin required for cell surface expression of blastocyst MHC

Blastocyst MHC is a mouse MHC class Ib gene that is selectively expressed in blastocysts and placenta like human HLA-G, which protect fetal trophoblasts and some tumor cells from NK cell attack, and in TAP-dependent expression on the cell surface. We expressed blastocyst MHC cDNA in beta2-deficient EL-4 S3 or beta2m-transfected EL-4 S3 cells. In parental EL-4 S3 cells, only 47-kDa blastocyst MHC protein was expressed and retained in the cytoplasm. However, additional 51-kDa blastocyst MHC protein was expressed on the surface of beta2m-transfected EL-4 S3 cells. The 51-kDa protein was resistant to Endo-H, whereas the 47-kDa protein was sensitive for Endo-H. The results suggested that beta2m as well as TAP was necessary for the transportation of blastocyst MHC from endoplasmic reticulum to cell surfaces through the Golgi apparatus, similar to other MHC class I molecules.     

O(2)- and H(2)O(2)-dependent verdoheme degradation by heme oxygenase: reaction mechanisms and potential physiological roles of the dual pathway degradation

Heme oxygenase (HO) catalyzes the catabolism of heme to biliverdin, CO, and a free iron through three successive oxygenation steps. The third oxygenation, oxidative degradation of verdoheme to biliverdin, has been the least understood step despite its importance in regulating HO activity. We have examined in detail the degradation of a synthetic verdoheme IXalpha complexed with rat HO-1. Our findings include: 1) HO degrades verdoheme through a dual pathway using either O(2) or H(2)O(2); 2) the verdoheme reactivity with O(2) is the lowest among the three O(2) reactions in the HO catalysis, and the newly found H(2)O(2) pathway is approximately 40-fold faster than the O(2)-dependent verdoheme degradation; 3) both reactions are initiated by the binding of O(2) or H(2)O(2) to allow the first direct observation of degradation intermediates of verdoheme; and 4) Asp(140) in HO-1 is critical for the verdoheme degradation regardless of the oxygen source. On the basis of these findings, we propose that the HO enzyme activates O(2) and H(2)O(2) on the verdoheme iron with the aid of a nearby water molecule linked with Asp(140). These mechanisms are similar to the well established mechanism of the first oxygenation, meso-hydroxylation of heme, and thus, HO can utilize a common architecture to promote the first and third oxygenation steps of the heme catabolism. In addition, our results infer the possible involvement of the H(2)O(2)-dependent verdoheme degradation in vivo, and potential roles of the dual pathway reaction of HO against oxidative stress are proposed.     

Dynamic induction of ADAMTS1 gene in the early phase of acute myocardial infarction

Extracellular matrix (ECM)-degrading enzymes such as matrix metalloproteases (MMPs) play an essential role in the repair of infarcted tissue, which affects ventricular remodeling after myocardial infarction. ADAMTS1 (A disintegrin and metalloprotease with thrombospondin motifs), a newly discovered metalloprotease, was originally cloned from a cancer cell line, but little is known about its contribution to disease. To test the hypothesis that ADAMTS1 appears in infarcted myocardial tissue, we examined ADAMTS1 mRNA expression in a rat myocardial infarction model by Northern blotting, real-time RT-PCR and in situ hybridization. Normal endothelium expressed little ADAMTS1 mRNA, while normal myocardium expressed no detectable ADAMTS1 mRNA. Up-regulation of ADAMTS1 was demonstrated by Northern blot analysis and real-time RT-PCR at 3 h after coronary artery ligation. In situ hybridization revealed strong ADAMTS1 mRNA signals in the endothelium and myocardium in the infarcted heart, mainly in the infarct zone, at 3 h after myocardial infarction. The rapid and transient up-regulation of the ADAMTS1 gene in the ischemic heart was distinct from the regulatory patterns of other MMPs. Our study demonstrated that the ADAMTS1 gene is a new early immediate gene expressed in the ischemic endothelium and myocardium.     

Laminin-based cell adhesion anchors microtubule plus ends to the epithelial cell basal cortex through LL5α/β

LL5β has been identified as a microtubule-anchoring factor that attaches EB1/CLIP-associating protein (CLASP)–bound microtubule plus ends to the cell cortex. In this study, we show that LL5β and its homologue LL5α (LL5s) colocalize with autocrine laminin-5 and its receptors, integrins α3β1 and α6β4, at the basal side of fully polarized epithelial sheets. Depletion of both laminin receptor integrins abolishes the cortical localization of LL5s, whereas LL5 depletion reduces the amount of integrin α3 at the basal cell cortex. Activation of integrin α3 is sufficient to initiate LL5 accumulation at the cell cortex. LL5s form a complex with the cytoplasmic tails of these integrins, but their interaction might be indirect. Analysis of the three-dimensional distribution of microtubule growth by visualizing EB1-GFP in epithelial sheets in combination with RNA interference reveals that LL5s are required to maintain the density of growing microtubules selectively at the basal cortex. These findings reveal that signaling from laminin–integrin associations attaches microtubule plus ends to the epithelial basal cell cortex.     

Distinct contributions of vacuolar Qabc- and R-SNARE proteins to membrane fusion specificity

In eukaryotic endomembrane systems, Qabc-SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) on one membrane and R-SNARE on the opposing membrane assemble into a trans-QabcR-SNARE complex to drive membrane fusion. However, it remains ambiguous whether pairing of Qabc- and R-SNAREs mediates membrane fusion specificity. Here, we explored the fusion specificity of reconstituted proteoliposomes bearing purified SNAREs in yeast vacuoles and other organelles. We found that not only vacuolar R-SNARE Nyv1p but also the non-cognate R-SNAREs, endosomal Snc2p, and endoplasmic reticulum-Golgi Sec22p caused efficient fusion with vacuolar Qabc-SNAREs. In contrast, their fusion is blocked completely by replacing vacuolar Qc-SNARE Vam7p with the non-cognate endosomal Tlg1p and Syn8p, although these endosomal Qc-SNAREs fully retained the ability to form cis-SNARE complexes with vacuolar SNAREs in solution and on membranes. Thus, our current study establishes that an appropriate assembly of Qabc-SNAREs is crucial for regulating fusion specificity, whereas R-SNARE itself has little contribution to specificity.