Sustained increase of alpha7 nicotinic receptors and choline-induced improvement of learning deficit in STOP knock-out mice.

International audienceMice deficient in the microtubule stabilizing protein STOP (stable tubule only polypeptide) show synaptic plasticity anomalies in hippocampus, dopamine hyper-reactivity in the limbic system and severe behavioral deficits. Some of these disturbances are alleviated by long-term antipsychotic treatment. Therefore, this mouse line represents a pertinent model for some aspects of schizophrenia symptomatology. Numerous data support dysfunction of nicotinic neurotransmission in schizophrenia and epidemiological studies show increased tobacco use in schizophrenic patients, in whom nicotine has been reported to improve cognitive deficits and impairment in sensory gating. In this study, we examined potential alterations in cholinergic (ACh) and nicotinic components and functions in STOP mutant mice. STOP KO mice displayed no variation of the density of ACh esterase and beta2* nicotinic receptors (nAChRs), large reductions in the density of vesicular ACh transporter and alpha6* nAChRs and marked increases in the density of alpha7 nAChRs, in some brain areas. STOP KO mice were hypersensitive to the stimulating locomotor effect of nicotine and, interestingly, their impaired performance in learning the cued version of the water maze were improved by administration of the preferential alpha7 nAChR agonist choline. Altogether, our data show that the deletion of the ubiquitous STOP protein elicited restricted alterations in ACh components. They also suggest that nicotinic neurotransmission can be deficient in STOP KO mice and that mutant mice can represent a meaningful model to study some nicotinic dysfunctions and therapeutic treatments

Microtubule-associated STOP protein deletion triggers restricted changes in dopaminergic neurotransmission.: Accumbic DA system in STOP KO mice

International audienceThe microtubule-associated stable tubule only polypeptide (STOP) protein plays a key-role in neuron architecture and synaptic plasticity. Recent studies suggest that schizophrenia is associated with alterations in the synaptic connectivity. Mice invalidated for the STOP gene display phenotype reminiscent of some schizophrenic-like symptoms, such as behavioral disturbances, dopamine (DA) hyper-reactivity, and possible hypoglutamatergia, partly improved by antipsychotic treatment. In the present work, we examined potential alterations in some DAergic key proteins and behaviors in STOP knockout mice. Whereas the densities of the DA transporter, the vesicular monoamine transporter and the D(1) receptor were not modified, the densities of the D(2) and D(3) receptors were decreased in some DAergic regions in mutant versus wild-type mice. Endogenous DA levels were selectively decreased in DAergic terminals areas, although the in vivo DA synthesis was diminished both in cell bodies and terminal areas. The DA uptake was decreased in accumbic synaptosomes, but not significantly altered in striatal synaptosomes. Finally, STOP knockout mice were hypersensitive to acute and subchronic locomotor effects of cocaine, although the drug equally inhibited DA uptake in mutant and wild-type mice. Altogether, these data showed that deletion of the ubiquitous STOP protein elicited restricted alterations in DAergic neurotransmission, preferentially in the meso-limbic pathway

Loss of STOP Protein Impairs Peripheral Olfactory Neurogenesis

International audienceIn conclusion, STOP protein seems to be involved in the establishment of synapses in the olfactory glomerulus. Our results indicate that the olfactory system of STOP null mice is a well-suited experimental model (1) for the study of the mechanism of action of STOP protein in synaptic function/plasticity and (2) for pathophysiological studies of the mechanisms of altered neuronal connections in schizophrenia

Ceramide in beta cells apoptosis induced by gluco-lipotoxicity:possible role of cer flow for the biosynthesis of complex sphingolipids

CERAMIDE IN BETA CELLS APOPTOSIS INDUCED BY GLUCO-LIPOTOXICITY: POSSIBLE ROLE OF CER FLOW FOR THE BIOSYNTHESIS OF COMPLEX SPHINGOLIPIDS P. Giussani1, H. Le Stunff2, E. Gjoni1, J. Veret2, L. Riboni1, P. Viani1 1Department of Medical Chemistry, Biochemistry and Biotechnology, University of Milano, LITA Segrate, Via Fratelli Cervi, 93, 20090 Segrate (MI) Italy 2Unit\ue9 Biologie Fonctionnelle et Adaptative - EAC CNRS 4413, Laboratoire de Biologie et Pathologie du Pancr\ue9as Endocrine, Universit\ue9 PARIS- DIDEROT (7),4, rue Marie-Andr\ue9e Lagroua Weill-Halle, 75205 PARIS Cedex 13 France Background: In type 2 diabetes the detrimental effects of chronic exposure to NEFA, in particular palmitate, on beta cell function and viability have been correlated to hyperglycaemia. De novo synthesis of ceramide (Cer) and ER stress are among the molecular pathways and regulators involved in these negative effects. In order to gain insight into the molecular mechanism(s) of gluco-lipotoxicity we studied the effect of palmitate and high glucose concentrations on ceramide metabolism in INS-1 cells. Results: The results obtained demonstrated that in INS-1 cells palmitate and glucose taken separately did not induce cell death, whereas the combined treatment with both nutrients resulted in an extensive cell apoptosis and this was associated to a significant increase of Cer levels. The presence of fumonisin-B1 partially reversed the apoptosis induced by the combined treatment with palmitate and glucose thus suggesting a role for ER-associated Cer in gluco-lipotoxicity in INS-1 cells. Metabolic studies show that treatment with palmitate results in the inhibition of Cer utilization for SM biosynthesis. Fluorescence microscopy studies suggest a reduced ER to Golgi flow of Cer. To evaluate if Cer accumulation could be due to a defect in the vesicular and/or CERT-mediated transport of Cer, we studied Cer metabolism in INS-1 cells silenced for CERT incubated with glucose in the presence or not of palmitate. In downregulated cells palmitate inhibited Cer utilization for SM biosynthesis; these results indicated that the vesicle-mediated transport is involved in the reduced ER to Golgi flow of Cer. Conclusions: Altogether these data suggest that the accumulation of Cer can be due to a decrease in utilization of newly synthesized Cer for SM biosynthesis thus supporting a role of ER-associated Cer in the regulation of beta cell death induced by gluco-lipotoxicity

Flow visualization Chapter12 : shadowgraph and schlieren; chapter 13 : interferometry; chapter 14 : light sheet technique

Published in 'Handbook of flow visualization' (p.189-217) under supervision of Prof. Wen Jei Yang (Univ. of Michigan, Ann Arbor, USA); ed. by Hemisphere publ. compSIGLEAvailable at INIST (FR), Document Supply Service, under shelf-number : 22419, issue : a.1990 n.193 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc