Developmental Changes of Human Neural Progenitor Cells Grafted into the Ventricular System and Prefrontal Cortex of Mouse Brain in Utero.

The transplantation of neural progenitors into a host brain represents a useful tool to evaluate the involvement of cell-autonomous processes and host local cues in the regulation of neuronal differentiation during the development of the mammalian brain. Human brain development starts at the embryonic stages, in utero, with unique properties at its neotenic stages. We analyzed the engraftment and differentiation of human neuronal progenitor cells (hNPCs) transplanted in utero into the mouse brain.

A chimeric mouse model to study human iPSC-derived neurons: the case of a truncating SHANK3 mutation.

Using human induced pluripotent stem cells (iPSC), recent studies have shown that the events underlying autism spectrum disorders (ASD) can occur during neonatal development. We previously analyzed the iPSC-derived pyramidal cortical neurons of a subset of patients with ASD carrying de novo heterozygous mutations in postsynaptic SHANK3 protein, in culture. We reported altered spinogenesis of those neurons.

Genetic susceptibility to nicotine addiction: Advances and shortcomings in our understanding of the CHRNA5/A3/B4 gene cluster contribution.

Over the last decade, robust human genetic findings have been instrumental in elucidating the heritable basis of nicotine addiction (NA). They highlight coding and synonymous polymorphisms in a cluster on chromosome 15, encompassing the CHRNA5, CHRNA3 and CHRNB4 genes, coding for three subunits of the nicotinic acetylcholine receptor (nAChR). They have inspired an important number of preclinical studies, and will hopefully lead to the definition of novel drug targets for treating NA.

Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations.

The synaptic protein SHANK3 encodes a multidomain scaffold protein expressed at the postsynaptic density of neuronal excitatory synapses. We previously identified de novo SHANK3 mutations in patients with autism spectrum disorders (ASD) and showed that SHANK3 represents one of the major genes for ASD. Here, we analyzed the pyramidal cortical neurons derived from induced pluripotent stem cells from four patients with ASD carrying SHANK3 de novo truncating mutations.

Induced pluripotent stem cells as a tool to study brain circuits in autism-related disorders.

The mammalian brain is a very complex organ containing an estimated 200 billion cells in humans. Therefore, studying human brain development has become very challenging given all the data that are available from different approaches, notably genetic studies.Recent pluripotent stem cell methods have given rise to the possibility of modeling neurodevelopmental diseases associated with genetic defects.

Three-dimensional Quantification of Dendritic Spines from Pyramidal Neurons Derived from Human Induced Pluripotent Stem Cells.

Dendritic spines are small protrusions that correspond to the post-synaptic compartments of excitatory synapses in the central nervous system. They are distributed along the dendrites. Their morphology is largely dependent on neuronal activity, and they are dynamic.

Contactin 4, -5 and -6 differentially regulate neuritogenesis while they display identical PTPRG binding sites.

The neural cell-adhesion molecules contactin 4, contactin 5 and contactin 6 are involved in brain development, and disruptions in contactin genes may confer increased risk for autism spectrum disorders (ASD). We describe a co-culture of rat cortical neurons and HEK293 cells overexpressing and delivering the secreted forms of rat contactin 4-6. We quantified their effects on the length and branching of neurites.

Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure.

Loss or dysfunction of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) leads to impairment of airway mucus transport and to chronic lung diseases resulting in progressive respiratory failure. Nicotinic acetylcholine receptors (nAChRs) bind nicotine and nicotine-derived nitrosamines and thus mediate many of the tobacco-related deleterious effects in the lung. Here we identify α7 nAChR as a key regulator of CFTR in the airways.

Alpha7-nicotinic receptors modulate nicotine-induced reinforcement and extracellular dopamine outflow in the mesolimbic system in mice.

Rationale: Nicotine is the main addictive component of tobacco and modifies brain function via its action on neuronal acetylcholine nicotinic receptors (nAChRs). The mesolimbic dopamine (DA) system, where neurons of the ventral tegmental area (VTA) project to the nucleus accumbens (ACb), is considered a core site for the processing of nicotine's reinforcing properties. However, the precise subtypes of nAChRs that mediate the rewarding properties of nicotine and that contribute to the development of addiction remain to be identified.

Antibodies against extracellular domains of α4 and α7 subunits alter the levels of nicotinic receptors in the mouse brain and affect memory: possible relevance to Alzheimer's pathology.

Nicotinic acetylcholine receptors (nAChRs) of α4β2 and α7 subtypes expressed in the brain neurons are involved in regulating memory and cognition. Their level is decreased upon several neurodegenerative disorders including Alzheimer's disease (AD), although the reasons for such a decrease are not completely understood. To test whether the nAChR-specific antibodies can affect the brain nAChRs and influence the behavior, we either immunized mice with recombinant extracellular domains of α4 and α7, subunits α4(1-209) and α7(1-208), or injected them with α7(1-208)-specific antibodies.

Functional effects of antibodies against non-neuronal nicotinic acetylcholine receptors.

Non-neuronal nicotinic acetylcholine receptors (nAChRs) are expressed in the spleen and regulate B lymphocyte propagation and activation. The aim of the present study was to investigate the cellular and physiological effects of antibodies against alpha4(1-209) and alpha7(1-208) nAChR extracellular domains. The antibodies, added in vitro, produced in vivo or injected, specifically bound mouse spleen B lymphocytes.

{alpha}7 nicotinic acetylcholine receptor regulates airway epithelium differentiation by controlling basal cell proliferation.

Airway epithelial basal cells are known to be critical for regenerating injured epithelium and maintaining tissue homeostasis. Recent evidence suggests that the alpha7 nicotinic acetylcholine receptor (nAChR), which is highly permeable to Ca(2+), is involved in lung morphogenesis. Here, we have investigated the potential role of the alpha7 nAChR in the regulation of airway epithelial basal cell proliferation and the differentiation of the human airway epithelium.

Regional changes in the cholinergic system in mice lacking monoamine oxidase A.

Elevated brain monoamine concentrations resulting from monoamine oxidase A genetic ablation (MAOA knock-out mice) lead to changes in other neurotransmitter systems. To investigate the consequences of MAOA deficiency on the cholinergic system, we measured ligand binding to the high-affinity choline transporter (CHT1) and to muscarinic and nicotinic receptors in brain sections of MAOA knock-out (KO) and wild-type mice. A twofold increase in [(3)H]-hemicholinium-3 ([(3)H]-HC-3) binding to CHT1 was observed in the caudate putamen, nucleus accumbens, and motor cortex in MAOA KO mice as compared with wild-type (WT) mice.

Sevoflurane anesthesia alters exploratory and anxiety-like behavior in mice lacking the beta2 nicotinic acetylcholine receptor subunit.

Background: Preexisting cognitive impairment and advanced age are factors that increase the risk of developing postoperative cognitive dysfunction. Because anesthetic agents interfere with cholinergic transmission and as impairment of cholinergic function is associated with cognitive decline, the authors studied how the volatile anesthetic sevoflurane affects exploratory and anxiety-like behavior in young and aged animals with a genetically modified cholinergic system.

Methods: Young and aged wild-type and mutant mice lacking the beta2 subunit of the nicotinic cholinergic receptor (beta2KO) were anesthetized for 2 h with 2.

Regional differential effects of chronic nicotine on brain alpha 4-containing and alpha 6-containing receptors.

Chronic nicotine upregulates central nicotinic acetylcholine receptors (nAChRs), a plasticity process thought to contribute to its addictive properties. To analyze this process in vivo, we chronically exposed mice to nicotine using minipump delivering nicotine at concentrations close to those found in tobacco smokers. Binding studies show upregulation of high-affinity nAChRs after 21 days of treatment in cortical areas, caudate putamen, nucleus accumbens, hippocampus, ventral tegmental area, and superior colliculi.

Long-term effects of chronic nicotine exposure on brain nicotinic receptors.

Chronic nicotine exposure results in long-term homeostatic regulation of nicotinic acetylcholine receptors (nAChRs) that play a key role in the adaptative cellular processes leading to addiction. However, the relative contribution of the different nAChR subunits in this process is unclear. Using genetically modified mice and pharmacological manipulations, we provide behavioral, electrophysiological, and pharmacological evidence for a long-term mechanism by which chronic nicotine triggers opposing processes differentially mediated by beta2*- vs.

Nicotine and serotonin in immune regulation and inflammatory processes: a perspective.

Nicotine and serotonin modulate the innate and adaptive immune responses and the inflammatory states. Several nicotinic cholinergic and serotonergic receptor subtypes have been characterized in B and T lymphocytes, monocytes, macrophages, and dendritic cells. The use of knockout mice has allowed a better characterization of nicotinic receptors and their role in anti-inflammatory processes in these cells.

alpha3alpha5beta2-Nicotinic acetylcholine receptor contributes to the wound repair of the respiratory epithelium by modulating intracellular calcium in migrating cells.

Nicotinic acetylcholine receptors (nAChRs), present in human bronchial epithelial cells (HBECs), have been shown in vitro to modulate cell shape. Because cell spreading and migration are important mechanisms involved in the repair of the bronchial epithelium, we investigated the potential role of nAChRs in the wound repair of the bronchial epithelium. In vivo and in vitro, alpha3alpha5beta2-nAChRs accumulated in migrating HBECs involved in repairing a wound, whereas alpha7-nAChRs were predominantly observed in stationary confluent cells.

Altered map of visual space in the superior colliculus of mice lacking early retinal waves.

During the development of the mammalian retinocollicular projection, a coarse retinotopic map is set up by the graded distribution of axon guidance molecules. Subsequent refinement of the initially diffuse projection has been shown to depend on the spatially correlated firing of retinal ganglion cells. In this scheme, the abolition of patterned retinal activity is not expected to influence overall retinotopic organization, but this has not been investigated.

5-HT activates ERK MAP kinase in cultured-human peripheral blood mononuclear cells via 5-HT1A receptors.

In the present work, we tested the hypothesis that serotonin (5-hydroxytryptamine = 5-HT) might activate the extracellular signal-regulated kinase (ERK) pathway in human peripheral blood mononuclear cells (PBMC). PBMC were maintained in culture for 72 hrs at 37 degrees C prior to the addition of 5-HT. Our results showed an increase in ERK activation by 5-HT with a peak effect at 30 min and maximal stimulation with 5-HT at 1microM.

Differential effect of serotonin on cytokine production in lipopolysaccharide-stimulated human peripheral blood mononuclear cells: involvement of 5-hydroxytryptamine2A receptors.

In order to provide additional insight into the in vivo significance of serotonin [5-hydroxytryptamine (5-HT)] in inflammation, we examined its effect on the production of tumor necrosis factor (TNF)-alpha, IL-1alpha, IL-1beta, IL-6, IL-10 and IL-1 receptor antagonist in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMC). 5-HT inhibited TNF-alpha production and increased IL-1beta production in PBMC. The level of IL-1beta-converting enzyme/caspase-1 remained unchanged, suggesting that the effect of 5-HT is not directly related to the IL-1beta maturation process.