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

Emergence and spread of SARS-CoV-2 lineage B.1.620 with variant of concern-like mutations and deletions.

Distinct SARS-CoV-2 lineages, discovered through various genomic surveillance initiatives, have emerged during the pandemic following unprecedented reductions in worldwide human mobility. We here describe a SARS-CoV-2 lineage - designated B.1.620 - discovered in Lithuania and carrying many mutations and deletions in the spike protein shared with widespread variants of concern (VOCs), including E484K, S477N and deletions HV69Δ, Y144Δ, and LLA241/243Δ. As well as documenting the suite of mutations this lineage carries, we also describe its potential to be resistant to neutralising antibodies, accompanying travel histories for a subset of European cases, evidence of local B.1.620 transmission in Europe with a focus on Lithuania, and significance of its prevalence in Central Africa owing to recent genome sequencing efforts there. We make a case for its likely Central African origin using advanced phylogeographic inference methodologies incorporating recorded travel histories of infected travellers

Les systèmes de neurotransmission centraux et leur implication dans les psychoses

Les pathologies psychiatriques ont une prévalence élevée et représentent un coût énorme pour la société en termes socio-économiques. Le rôle de la neurotransmission dopaminergique dans la schizophrénie est indubitable. Cependant, durant plusieurs décennies, des dysfonctions de cette transmission n'ont fait l'objet que de présomptions. C'est tout récemment que la nature de ces dysfonctions commence à être connue. Il paraît maintenant acquis que les perturbations de la transmission dopaminergique observées chez les schizophrènes ne sont pas responsables de l'étiologie de cette affection, mais sont plutôt la conséquence majeure d'autres dysfonctions. Si le rôle de la neurotransmission sérotoninergique dans les troubles de l'humeur est certain, son implication dans la schizophrénie repose encore sur des preuves indirectes et éparses. Enfin, l'implication de la neurotransmission glutamatergique dans la schizophrénie, longtemps ralentie par le manque d'outils sélectifs, repose maintenant sur des résultats intéressants, mais qui doivent impérativement être confirmés

Phénotype nicotinique des souris dépourvues du transporteur de la dopamine ou de la protéine STOP (modèles d'étude de symptômes psychiatriques)

La grande prévalence de fumeurs chez les patients souffrant d'hyperactivité avec trouble de l'attention (ADHD) et les schizophrènes suggère que cet abus de tabac constitue une forme d'auto-médication. Le but de ma thèse fut de caractériser le phénotype nicotinique de deux modèles animaux présentant des phénotypes associés à certains symptômes de la schizophrénie et/ou de l'ADHD : les souris invalidées pour le gène du transporteur de la dopamine (DAT KO) et les souris invalidées pour le gène de la protéine STOP (Stable Tubule Only Polypeptide ; STOP KO). Mon travail a notamment montré une hypersensibilité des souris DAT KO à l'effet locomoteur calmant de la nicotine, un rôle pro-cognitif de la nicotine et/ou d'agonistes nicotiniques a7 sur les déficits d'apprentissages des souris DAT KO et STOP KO et une absence de tolérance à ces effets chez les souris DAT KO. L'utilisation d'agonistes nicotiniques pourrait réduire les risques liés au fort tabagisme des patients ADHD et schizophrènes.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

Étude des partenaires protéiques du transporteur de la dopamine et caractérisation des phénotypes nicotinique et dopaminergique des souris invalidées pour le gène de la protéine STOP

Dans une première partie, j'ai tenté de carctériser l'interaction du transporteur de la dopamine avec deux protéines partenaires. Ensuite, j'ai étudié les souris invalidées pour le gène de la protéine associée aux microtubules STOP, qui pourraient constituer un modèle d'étude pour la schizophrénie. Étant donnée la forte prévalence de fumeurs chez les schizophrènes et l'implication de la dopamine dans cette pathologie, je me suis intéressée aux phénotypes nicotinique et dopaminergique de ces souris. Les mutants montrent des altérations de composants nicotiniques et cholinergiques, une hypersensibilité locomotrice à la nicotine et un déficit de mémoire associative, restauré par la choline, agoniste des récepteurs alpha7. En plus des anomalies de densité de récepteurs dopaminergiques, les mutants montrent une hypersensibilité à la cocaine et une sensibilisation comportementale à cette dorgue. Ces résultats incitent à approfondir l'étude de ce modèle animal pour la schizophrénie.In a first part, I tried to characterize the interaction between the dopamine transporter and two protein partners : ACIII and sh2bp1. In a second part, I studied mice devoice of the microtubule protein STOP, which could represent a pertinent model of schizophrenia. Given the high prevalence of smokers among schizophrenics and the implication of dopamine in this pathology, I decided to study the nicotinic and dopaminergic phenotypes of these mice. Mutant animals show alterations in the density of some nicotinic and cholinergic components, locomotor hypersensitivity to nicotine and defects in associative memory, reversed by administration of choline, an alpha7 receptor agonist. In addition to anomalies in the density of some dopaminergic receptors, mutant mice show a hypersensitivity to cocaine and a behavioural sensitization to this drug. This new data reinforce the pertinence of this model and support further experiments to complete the characterization of this model.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

The dopamine D1 receptor agonist SKF 38393 improves temporal order memory performance in maternally deprived rats

International audiencePreviously, we showed that maternal deprivation (MD) (3 h/day, postnatal-day 1-14) impaired the performance at adulthood in the object temporal order memory task (TMT) that principally implicates the medial prefrontal cortex (mPFC). Dopamine (DA) transmission in the PFC may play a critical role in the achievement of the TMT. Here, to investigate whether MD could results in dysfunction of the DA system in the mPFC, we assessed in this region the tissue contents and extracellular levels of DA and its metabolites, as the density of D1 receptor. Besides we examined whether an agonist of the DA receptor D1, the SKF38393, could have a beneficial effect on the performance of deprived (D) rats in the TMT. We observed that MD induced a significant reduction of the extracellular level of DOPAC in the mPFC and in the density of the D1 receptor in the anterior cingulate cortex, a sub-region of mPFC. On the other hand, we observed that an acute systemic injection of a D1 receptor agonist, SKF38393, was effective to correct the memory deficiency of D rats in the TMT, when administered before the retrieval phase. We showed that a stress suffered by rats during the perinatal period led to dysfunction of the adult DA system, possibly triggering greater vulnerability to cognitive and mood disorders. Interestingly, an acute administration of a D1 receptor agonist in adulthood was sufficient to improve the deficit in the temporal memory. A better understanding of this phenomenon would permit the development of treatments adapted to patients with a history of early traumatic experiences

Short Communication: Extremely Severe CD4 Lymphopenia During HIV-1 Primary Infection

International audienceWe report the case of a patient with a very profound CD4 T cell lymphopenia <20 cells/mm3 in the context of a primary HIV-1 infection, associated with both delayed HIV-specific antibody and CD8 T cell responses. A long-term immune reconstitution was observed after immediate initiation of antiretroviral therapy

Quantitative RT-PCR distribution of serotonin 5-HT6 receptor mRNA in the central nervous system of control or 5,7-dihydroxytryptamine-treated rats

International audiencePossible adaptive changes of the recently cloned serotonin 5-HT6 receptor after the selective lesion of serotoninergic neurons by an intracerebral administration of 5,7-dihydroxytryptamine were investigated using competitive RT-PCR (reverse transcription followed by polymerase chain reaction) for the measurement of 5-HT6-mRNA in various areas of the rat central nervous system. In control rats, 5-HT6-mRNA was the most abundant in the nucleus accumbens, followed by the olfactory tubercle and the striatum. High levels of 5-HT6-mRNA were also found in the hypothalamus and the hippocampus, whereas the cerebral cortex, the substantia nigra, and the spinal cord contained moderate levels of the transcript. Low but easily quantifiable levels of 5-HT6-mRNA were measured in the ventral tegmental area, the anterior raphe area, and the cerebellum. In addition, moderate to low levels of this mRNA were also found in dorsal root ganglia and the pituitary gland. Three weeks after the microinfusion of 5,7-dihydroxytryptamine into the anteroventral vicinity of the dorsal raphe nucleus in nomifensine-pretreated rats, the levels of serotonin transporter-mRNA were reduced by 90% in the anterior raphe area, as expected of the extensive lesion of serotoninergic neurons. In contrast, quantitative determinations of the 5-HT6-mRNA in this area as well as in the nucleus accumbens, the striatum, and the hippocampus indicated that its levels were not significantly different in 5,7-dihydroxytryptamine-treated rats and in controls. These data showed that the 5-HT6 receptor: 1) is not an autoreceptor, and 2) exhibits probably no up regulation in postsynaptic target cells after the selective degeneration of serotoninergic projections