Host-guided migration allows targeted introduction of neurons into the embryonic brain

AbstractThe stereotyped positions occupied by individual classes of neurons are a fundamental characteristic of CNS cytoarchitecture. To study the regulation of neuronal positioning, we injected genetically labeled neural precursors derived from dorsal and ventral mouse forebrain into the telencephalic vesicles of embryonic rats. Cells from both areas were found to participate in the generation of telencephalic, diencephalic, and mesencephalic brain regions. Donorderived neurons populated the host brain in distinct patterns and acquired phenotypic features appropriate for their final location. These observations indicate that neuronal migration and differentiation are predominantly regulated by non-cell-autonomous signals. Exploiting this phenomenon, intrauterine transplantation allows generation of controlled chimerism in the mammalian brain

Evidence for a protective effect of the loss of α4-containing nicotinic acetylcholine receptors on Aβ-related neuropathology in Tg2576 mice

International audienceIntroduction Loss of cholinergic neurons as well as α4β2* (* = containing) nicotinic acetylcholine receptors (nAChRs) is a prominent feature of Alzheimer’s disease (AD). Specifically, amyloid β (Aβ), the principal pathogenic factor of AD, is a high affinity ligand for nAChRs. Yet, the pathophysiological role of nAChRs in AD is not well established. Methods In the present study, we have investigated the effects of the loss of α4* nAChRs on the histological alterations of the Tg2576 mouse model of AD (APPswe) crossing hemizygous APPswe mice with mice carrying the genetic inactivation of α4 nAChR subunit (α4KO). Results A global decrease in Aβ plaque load was observed in the forebrain of APPswe/α4KO mice in comparison with APPswe mice, that was particularly marked in neocortex of 15 month-old mice. At the same age, several alterations in synaptophysin immunoreactivity were observed in cortico-hippocampal regions of APPswe mice that were partially counteracted by α4KO. The analysis of the immunoreactivity of specific astroglia (glial fibrillary acidic protein, GFAP) and microglia (ionized calcium-binding adapter molecule, Iba1) markers showed an increase in the number as well as in the area occupied by these cells in APPswe mice that were partially counteracted by α4KO. Conclusion Overall, the present histological study points to a detrimental role of α4* nAChRs that may be specific for Aβ-related neuropathology

Behavioral Sequence Analysis Reveals a Novel Role for ß2* Nicotinic Receptors in Exploration

Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central nervous system and modulate neuronal function in most mammalian brain structures. The contribution of defined nAChR subunits to a specific behavior is thus difficult to assess. Mice deleted for ß2-containing nAChRs (ß2−/−) have been shown to be hyperactive in an open-field paradigm, without determining the origin of this hyperactivity. We here develop a quantitative description of mouse behavior in the open field based upon first order Markov and variable length Markov chain analysis focusing on the time-organized sequence that behaviors are composed of. This description reveals that this hyperactivity is the consequence of the absence of specific inactive states or “stops”. These stops are associated with a scanning of the environment in wild-type mice (WT), and they affect the way that animals organize their sequence of behaviors when compared with stops without scanning. They characterize a specific “decision moment” that is reduced in ß2−/− mutant mice, suggesting an important role of ß2-nAChRs in the strategy used by animals to explore an environment and collect information in order to organize their behavior. This integrated analysis of the displacement of an animal in a simple environment offers new insights, specifically into the contribution of nAChRs to higher brain functions and more generally into the principles that organize sequences of behaviors in animals

EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF

EMMPRIN/CD147 is mainly known for its protease inducing function but a role in promoting tumor angiogenesis has also been demonstrated. This study provides evidence that EMMPRIN is a new coreceptor for the VEGFR-2 tyrosine kinase receptor in both endothelial and tumor cells, as it directly interacts with it and regulates its activation by its VEGF ligand, signalling and functional consequences both in vitro and in vivo. Computational docking analyses and mutagenesis studies identified a molecular binding site in the extracellular domain of EMMPRIN located close to the cell membrane and containing the amino acids 195/199. EMMPRIN is overexpressed in cancer and hence is able to further potentiate VEGFR-2 activation, suggesting that a combinatory therapy of an antiangiogenic drug together with an inhibitor of EMMPRIN/VEGFR-2 interaction may have a greater impact on inhibiting angiogenesis and malignancy.This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM), La Ligue Nationale contre le Cancer (LNCC), La Société Française de Dermatologie and Université Paris Diderot. F.K was supported by a PhD fellowship from Cancéropôle-Ile de France and from Fondation ARC pour la Recherche sur le Cancer. L.P.C was supported by a FPU fellowship from Spanish Ministry of Science. This work was supported by grant BIO2010–22324 from Plan NacionalI+D+iMICINN. We thank the core facility of the Institut Universitaire d’Hématologie for confocal microscopy analyses. The core facility is supported by grants from the Association Saint-Louis, Conseil Regional d’Ile-de-France, and the Ministère de la Recherche.Peer ReviewedPostprint (published version

Emerging concepts: novel integration of in vivo approaches to localize the function of nicotinic receptors.

International audienceNicotinic acetylcholine receptors (nAChRs) are important targets of the neuromodulator acetylcholine (ACh) and the drug nicotine. The role of their different subunits has been analysed for a decade by the creation of knock-out (KO) mice using homologous recombination. This technique shows that a given subunit is necessary for a given function. However, for ubiquitously expressed genes, it cannot demonstrate the localization for a given subunit in which its expression is sufficient, especially for behavioural phenotypes. Sufficient in this context means that the brain region requiring the expression of the gene product has been localized. Novel strategies have therefore been developed to re-express, region specifically, nAChR subunits on a KO background using lentiviral vectors. Localized regeneration of fully functional high-affinity nAChRs in defined brain regions has proven that these receptors are sufficient to restore a variety of functions: nicotine-induced dopamine release, nicotine self-administration in mice, dopamine neuron firing patterns, and exploratory and locomotor behaviours in a sequential locomotor task testing executive function were thus defined as depending exclusively on the 'knock-back' of beta2*-nAChRs into the ventral tegmental area. These analyses highlight the important role of endogenous cholinergic regulation of a variety of functions. The novel integrated use of restricted re-expressed nAChR subunits with in vivo electrophysiology and automated quantitative behavioural analysis enables the further analysis of defined neuronal circuits in nicotine addiction and higher cognitive function

The nicotinic receptor alpha5 coding polymorphism rs16969968 as a major target in disease: Functional dissection and remaining challenges

International audienceNicotinic acetylcholine receptors (nAChRs) are major signalling molecules in the central and peripheral nervous system. Over the last decade, they have been linked to a number of major human psychiatric and neurological conditions, like smoking, schizophrenia, Alzheimer's disease and many others. Human Genome-Wide Association Studies (GWAS) have robustly identified genetic alterations at a locus of chromosome 15q to several of these diseases. In this review, we discuss a major coding polymorphism in the alpha5 subunit, referred to as α5SNP, and its functional dissection in vitro and in vivo. Its presence at high frequency in many human populations lends itself to pharmaceutical intervention in the context of 'positive allosteric modulators' (PAMs). We will present the prospects of this novel treatment, and the remaining challenges to identify suitable molecules

Role of endogenous acetylcholine in the control of the dopaminergic system via nicotinic receptors.

International audienceNicotinic acetylcholine receptors (nAChRs) are pentameric membrane protein receptors activated by the addictive drug, nicotine. However, sometimes underestimated, under physiological conditions the endogenous neurotransmitter acetylcholine is the agonist. In this mini-review, I will discuss the evidence in favour of an important role for this cholinergic activation of the dopaminergic (DAergic) system. I will focus on the literature implicating the action of acetylcholine on the somato-dendritic compartment of these neurons. This modulation is responsible for a variety of phenotypes in knock-out animals of nAChR subunits. These include locomotion, exploratory behaviour, dopamine (DA) release, and DA neuron firing patterns. The novel techniques brought to bear on these analyses, lentiviral re-expression, and repression, of nAChR subunits, and transgenic expression of hypersensitive receptors will be discussed

Nouveaux modèles in vivo pour l'étude du rôle du recepteur nicotinique dans le stade précoce de la maladie d'Alzheimer

Alzheimer s disease (AD) is a neurodegenerative, which is predicted to become a major burden as our population ages. To investigate its underlying neurobiological mechanisms, different models of AD were developed. However, these models show some limitations. We have developed novel approaches to study the early phases of AD in the mouse brain. The first system we developed takes advantage of the lentiviral vector technology. We created a lentivirus that expresses the human amyloid precursor protein sequence harbouring 3 pathogenic mutations identified in patients, Swedish, London and Austrian. This vector injected into the mouse hippocampus is able to direct Aß synthesis and its accumulation, together with deficits in short term memory. The second model was obtained by injecting small Aß oligomers, called ADDLs, in vivo into the mouse brain. This approach allowed us to investigate the synaptic changes 24 hours post-injection of this toxic form of Aß. We observed a decrease in the post-synaptic markers PSD-95 and Drebrin in ADDLs injected mice. Once established the efficacy of our systems, we used them to investigate the role of nicotinic receptors in AD. We have combined the use of our systems with knock-out mouse lines for specific nicotinic subunits. We showed a possible role of the ß2 subunit in the memory loss mediated by the expression of hAPP in the hippocampus, and a role of the a7 subunit in ADDL-induced synaptic toxicity. The novel animal models of AD we developed during this work should provide a better understanding of the underlying biological mechanisms, and of the involvement of nicotinic receptors, notably in the early events occurring in this pathology.La maladie d Alzheimer est une maladie neurodegenerative et de nombreuses études montrent qu elle est la pathologie majeure de nos populations vieillissantes. Afin de pouvoir étudier les mécanismes neurobiologiques sous-jacents à cette pathologie, différents modèles ont été développés. L ensemble des modèles disponibles présentent des limitations. Au cours de cette thèse, nous avons mis au point de nouvelles approches pour étudier le stade précoce de la maladie dans le cerveau des souris. Le premier système que nous avons développé s appuie sur la technologie des vecteurs lentiviraux. Nous avons construit un lentivirus qui exprime la séquence du précurseur de la protéine amyloïde humaine contenant 3 mutations pathogens, Swedish, London et Austrian. Nous avons démontré que, lorsqu il est injecté dans l hippocampe des souris, ce vecteur est capable d induire l accumulation du peptide Aß, accompagnées d un déficit de mémoire à court terme. Le second modèle a été obtenu en injectant des petits oligomères d Aß, appelés ADDLs, in vivo dans le cerveau des souris. Cette approche, nous a permis d étudier les changements synaptiques induits par la forme toxique d Aß, 24 heures après l injection. Nous avons ainsi pu mettre en évidence une diminution de certain marqueurs post-synaptiques. Après avoir validé ces modèles nouvellement développés, nous les avons employés pour rechercher le rôle de certains récepteurs nicotiniques dans la maladie d Alzheimer. L utilisation de ces modèles animaux de la maladie d Alzheimer devrait permettre une meilleure compréhension de ses mécanismes biologiques sous-jacents et de l implication des récepteurs nicotiniques dans la phase précoce de la maladie.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment.

International audienceAlzheimer's Disease (AD) is the major form of senile dementia, characterized by neuronal loss, extracellular deposits, and neurofibrillary tangles. It is accompanied by a loss of cholinergic tone, and acetylcholine (ACh) levels in the brain, which were hypothesized to be responsible for the cognitive decline observed in AD. Current medication is restricted to enhancing cholinergic signalling for symptomatic treatment of AD patients. The nicotinic acetylcholine receptor family (nAChR) and the muscarinic acetylcholine receptor family (mAChR) are the target of ACh in the brain. Both families of receptors are affected in AD. It was demonstrated that amyloid beta (Aβ) interacts with nAChRs. Here we discuss how Aβ activates or inhibits nAChRs, and how this interaction contributes to AD pathology. We will discuss the potential role of nAChRs as therapeutic targets. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'