Hypoglutamatergic activity in the STOP knockout mouse: a potential model for chronic untreated schizophrenia.: 13C study of metabolism in STOP KO mice

International audienceIn mice, the deletion of the STOP protein leads to hyperdopaminergia and major behavioral disorders that are alleviated by neuroleptics, representing a potential model of schizophrenia. The reduction of the glutamatergic synaptic vesicle pool in the hippocampus could reflect a disturbance in glutamatergic neurotransmission in this model. Here we examined potential disturbances in energy metabolism and interactions between neurons and glia in 15-week-old STOP KO, wild-type, and heterozygous mice. Animals received [1-(13)C]glucose and [1,2-(13)C]acetate, the preferential substrates of neurons and astrocytes, respectively. Extracts from the whole forebrain and midbrain were analyzed by HPLC, (13)C and (1)H NMR spectroscopy. Amounts and labeling of most metabolites were unchanged. However, glutamine concentration and amount of [4,5-(13)C]glutamine derived from [1,2-(13)C]acetate significantly decreased by 17% and 18%, respectively, in STOP KO compared with wild-type mice. The amount of [4-(13)C]glutamate was decreased in STOP KO and heterozygous compared with wild-type mice. gamma-Aminobutyric acid labeling was not influenced by the genotype. Because STOP-deficient mice have a lower synaptic vesicle density, less glutamate is released to the synaptic cleft, leading to decreased stimulation of the postsynaptic glutamate receptors, reflecting increased glutamine metabolism only in the vicinity of the postsynapse of STOP KO mice

Both chronic treatments by epothilone D and fluoxetine increase the short-term memory and differentially alter the mood status of STOP/MAP6 KO mice.: epothilone and fluoxetine improve STOP KO memory

International audienceRecent evidence underlines the crucial role of neuronal cytoskeleton in the pathophysiology of psychiatric diseases. In this line, the deletion of STOP/MAP6 (Stable Tubule Only Polypeptide), a microtubule-stabilizing protein, triggers various neurotransmission and behavioral defects, suggesting that STOP knockout (KO) mice could be a relevant experimental model for schizoaffective symptoms. To establish the predictive validity of such a mouse line, in which the brain serotonergic tone is dramatically imbalanced, the effects of a chronic fluoxetine treatment on the mood status of STOP KO mice were characterized. Moreover, we determined the impact, on mood, of a chronic treatment by epothilone D, a taxol-like microtubule-stabilizing compound that has previously been shown to improve the synaptic plasticity deficits of STOP KO mice. We demonstrated that chronic fluoxetine was either antidepressive and anxiolytic, or pro-depressive and anxiogenic, depending on the paradigm used to test treated mutant mice. Furthermore, control-treated STOP KO mice exhibited paradoxical behaviors, compared with their clear-cut basal mood status. Paradoxical fluoxetine effects and control-treated STOP KO behaviors could be because of their hyper-reactivity to acute and chronic stress. Interestingly, both epothilone D and fluoxetine chronic treatments improved the short-term memory of STOP KO mice. Such treatments did not affect the serotonin and norepinephrine transporter densities in cerebral areas of mice. Altogether, these data demonstrated that STOP KO mice could represent a useful model to study the relationship between cytoskeleton, mood, and stress, and to test innovative mood treatments, such as microtubule-stabilizing compounds

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

Chronic administration of atypical antipsychotics improves behavioral and synaptic defects of STOP null mice.

International audienceINTRODUCTION: Recent studies have suggested that schizophrenia is associated with alterations in the synaptic connectivity involving cytoskeletal proteins. The microtubule-associated protein stable tubule only polypeptide (STOP) plays a key role in neuronal architecture and synaptic plasticity, and it has been demonstrated that STOP gene deletion in mice leads to a phenotype mimicking aspects of positive and negative symptoms and cognitive deficits classically observed in schizophrenic patients. In STOP null mice, behavioral defects are associated with synaptic plasticity abnormalities including defects in long-term potentiation. In these mice, long-term administration of typical antipsychotics has been shown to partially alleviate behavioral defects but, as in humans, such a treatment was poorly active on deficits related to negative symptoms and cognitive impairments. Here, we assessed the effects of risperidone and clozapine, two atypical antipsychotics, on STOP null mice behavior and synaptic plasticity. RESULTS: Long-term administration of either drug results in alleviation of behavioral alterations mimicking some negative symptoms and partial amelioration of some cognitive defects in STOP null mice. Interestingly, clozapine treatment also improves synaptic plasticity of the STOP null animals by restoring long-term potentiation in the hippocampus. DISCUSSION: All together, the pharmacological reactivity of STOP null mice to antipsychotics evokes the pharmacological response of humans to such drugs. Totally, our study suggests that STOP null mice may provide a useful preclinical model to evaluate pharmacological properties of antipsychotic drugs

The stop null mice model for schizophrenia displays [corrected] cognitive and social deficits partly alleviated by neuroleptics.

International audienceRecently evidence has accumulated that schizophrenia can arise from primary synaptic defects involving structural proteins particularly, microtubule associated proteins. Previous experiments have demonstrated that a STOP (stable tubule only peptide) gene deletion in mice leads to a phenotype mimicking some aspects of positive symptoms classically observed in schizophrenic patients. In the current study, we determined if STOP null mice demonstrate behavioral abnormalities related to the social and cognitive impairments of schizophrenia. Compared with wild-type mice, STOP null mice exhibited deficits in the non-aggressive component of social recognition, short term working memory and social and spatial learning. As described in humans, learning deficits in STOP null mice were poorly sensitive to long term treatment with typical neuroleptics. Since social and cognitive dysfunction have consistently been considered as central features of schizophrenia, we propose that STOP null mice may provide a useful model to understand the neurobiological correlates of social and cognitive defects in schizophrenia and to develop treatments that better target these symptoms

Abnormal nociception and opiate sensitivity of STOP null mice exhibiting elevated levels of the endogenous alkaloid morphine

<p>Abstract</p> <p>Background-</p> <p>Mice deficient for the stable tubule only peptide (STOP) display altered dopaminergic neurotransmission associated with severe behavioural defects including disorganized locomotor activity. Endogenous morphine, which is present in nervous tissues and synthesized from dopamine, may contribute to these behavioral alterations since it is thought to play a role in normal and pathological neurotransmission.</p> <p>Results-</p> <p>In this study, we showed that STOP null brain structures, including cortex, hippocampus, cerebellum and spinal cord, contain high endogenous morphine amounts. The presence of elevated levels of morphine was associated with the presence of a higher density of mu opioid receptor with a higher affinity for morphine in STOP null brains. Interestingly, STOP null mice exhibited significantly lower nociceptive thresholds to thermal and mechanical stimulations. They also had abnormal behavioural responses to the administration of exogenous morphine and naloxone. Low dose of morphine (1 mg/kg, i.p.) produced a significant mechanical antinociception in STOP null mice whereas it has no effect on wild-type mice. High concentration of naloxone (1 mg/kg) was pronociceptive for both mice strain, a lower concentration (0.1 mg/kg) was found to increase the mean mechanical nociceptive threshold only in the case of STOP null mice.</p> <p>Conclusions-</p> <p>Together, our data show that STOP null mice displayed elevated levels of endogenous morphine, as well as an increase of morphine receptor affinity and density in brain. This was correlated with hypernociception and impaired pharmacological sensitivity to mu opioid receptor ligands.</p

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

Les parures de cartonnage des momies d'une nécropole d'Ismant el-Kharab

Description des parures de cartonnage mises au jour dans 18 sur 27 tombes fouillées à Ismant (oasis de Dakhleh): d'après leur style, elles s'échelonnent de l'époque romaine au 3e s. ap. J.-C.; leur iconographie se rattache aux anciennes croyances religieuses égyptiennes

Les parures de cartonnage des momies égyptiennes, de Saqqara aux Oasis ; Programmes iconographique et théologique

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