Divergent Roles of p75NTR and Trk Receptors in BDNF's Effects on Dendritic Spine Density and Morphology

Activation of TrkB receptors by brain-derived neurotrophic factor (BDNF) followed by MAPK/ERK signaling increases dendritic spine density and the proportion of mature spines in hippocampal CA1 pyramidal neurons. Considering the opposing actions of p75NTR and Trk receptors in several BDNF actions on CNS neurons, we tested whether these receptors also have divergent actions on dendritic spine density and morphology. A function-blocking anti-p75NTR antibody (REX) did not affect spine density by itself but it prevented BDNF's effect on spine density. Intriguingly, REX by itself increased the proportion of immature spines and prevented BDNF's effect on spine morphology. In contrast, the Trk receptor inhibitor k-252a increased spine density by itself, and prevented BDNF from further increasing spine density. However, most of the spines in k-252a-treated slices were of the immature type. These effects of k-252a on spine density and morphology required neuronal activity because they were prevented by TTX. These divergent BDNF actions on spine density and morphology are reminiscent of opposing functional signaling by p75NTR and Trk receptors and reveal an unexpected level of complexity in the consequences of BDNF signaling on dendritic morphology

HDAC activity is required for BDNF to increase quantal neurotransmitter release and dendritic spine density in CA1 pyramidal neurons

Molecular mechanisms involved in the strengthening and formation of synapses include the activation and repression of specific genes or subsets of genes by epigenetic modifications that do not alter the genetic code itself. Chromatin modifications mediated by histone acetylation have been shown to be critical for synaptic plasticity at hippocampal excitatory synapses and hippocampal-dependent memory formation. Considering that brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity and behavioral adaptations, it is not surprising that regulation of this gene is subject to histone acetylation changes during synaptic plasticity and hippocampal-dependent memory formation. Whether the effects of BDNF on dendritic spines and quantal transmitter release require histone modifications remains less known. By using two different inhibitors of histone deacetylases (HDACs), we describe here that their activity is required for BDNF to increase dendritic spine density and excitatory quantal transmitter release onto CA1 pyramidal neurons in hippocampal slice cultures. These results suggest that histone acetylation/deacetylation is a critical step in the modulation of hippocampal synapses by BDNF. Thus, mechanisms ofepigenetic modulation of synapse formation and function are novel targets to consider for the amelioration of symptoms of intellectual disabilities and neurodegenerative disorders associated with cognitive and memory deficits. © 2011 Wiley Periodicals, Inc.Fil: Calfa, Gaston Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. University of Alabama at Birmingahm; Estados Unidos. The University of Alabama at Birmingham. Civitan International Research Center. Department of Neurobiology; Estados UnidosFil: Chapleau, Christopher A.. University of Alabama at Birmingahm; Estados Unidos. The University of Alabama at Birmingham. Civitan International Research Center. Department of Neurobiology; Estados UnidosFil: Campbell, Susan. The University of Alabama at Birmingham. Civitan International Research Center. Department of Neurobiology; Estados Unidos. University of Alabama at Birmingahm; Estados UnidosFil: Inoue, Takafumi. Waseda University. Faculty of Science and Engineering. Department of Life Science and Medical Bioscience; JapónFil: Morse, Sarah J.. The University of Alabama at Birmingham. Civitan International Research Center. Department of Neurobiology; Estados Unidos. University of Alabama at Birmingahm; Estados UnidosFil: Lubin, Farah D.. University of Alabama at Birmingahm; Estados Unidos. The University of Alabama at Birmingham. Civitan International Research Center. Department of Neurobiology; Estados UnidosFil: Pozzo-Miller, Lucas. The University of Alabama at Birmingham. Civitan International Research Center. Department of Neurobiology; Estados Unidos. University of Alabama at Birmingahm; Estados Unido

Cluster-randomized non-inferiority trial to compare supplement consumption and adherence to different dosing regimens for antenatal calcium and iron-folic acid supplementation to prevent preeclampsia and anaemia: rationale and design of the Micronutrient Initiative study

Background: To prevent pre-eclampsia in populations with insufficient dietary calcium (Ca) intake, the World Health Organisation (WHO) recommends routine Ca supplementation during antenatal care (ANC). WHO guidelines suggest a complex dosing regimen, requiring as many as 5 pill-taking events per day when combined with iron and folic acid (IFA) supplements. Poor adherence may undermine public health effectiveness, so simpler regimens may be preferable. This trial will compare the effect of the WHO-recommended (higher-dose) regimen vs. a simpler, lower-dose regimen on supplement consumption and pill-taking behaviours in Kenyan ANC clients. Design and methods: This is a parallel, non-inferiority, cluster-randomized trial; we examined 16 primary care health facilities in Kenya, 1047 pregnant women between 16-30 weeks gestational age. Higher-dose regimen: 1.5 g elemental calcium in 3 separate doses (500 mg Ca/pill) and IFA (60 mg Fe + 400 μg folic acid) taken with evening dose. Lower-dose regimen: 1.0 g calcium in 2 separate doses (500 mg Ca/pill) with IFA taken as above. Measurements: Primary outcome is Ca pills consumed per day, measured by pill counts. Secondary outcomes include IFA pills consumed per day, client knowledge, motivation, social support, and satisfaction, measured at 4 to 10 weeks post-enrolment. Statistical analyses: Unit of randomization is the health-care facility; unit of analysis is individual client. Intent-to-treat analysis will be implemented with multi-level models to account for clustering. Expected public health impact: If pregnant women prescribed lower doses of Ca ingest as many pills as women prescribed the WHO-recommended regimen, developing a lower-dose recommendation for antenatal Ca and IFA supplementation programs could save resources

The Endosome Localized Arf-GAP AGAP1 Modulates Dendritic Spine Morphology Downstream of the Neurodevelopmental Disorder Factor Dysbindin

AGAP1 is an Arf1 GTPase activating protein that interacts with the vesicle-associated protein complexes adaptor protein 3 (AP-3) and Biogenesis of Lysosome Related Organelles Complex-1 (BLOC-1). Overexpression of AGAP1 in non-neuronal cells results in an accumulation of endosomal cargoes, which suggests a role in endosome-dependent traffic. In addition, AGAP1 is a candidate susceptibility gene for two neurodevelopmental disorders, autism spectrum disorder (ASD) and schizophrenia (SZ); yet its localization and function in neurons have not been described. Here, we describe that AGAP1 localizes to axons, dendrites, dendritic spines, and synapses, colocalizing preferentially with markers of early and recycling endosomes. Functional studies reveal overexpression and down-regulation of AGAP1 affects both neuronal endosomal trafficking and dendritic spine morphology, supporting a role for AGAP1 in the recycling endosomal trafficking involved in their morphogenesis. Finally, we determined the sensitivity of AGAP1 expression to mutations in the DTNBP1 gene, which is associated with neurodevelopmental disorder, and found that AGAP1 mRNA and protein levels are selectively reduced in the null allele of the mouse orthologue of DTNBP1. We postulate that endosomal trafficking contributes to the pathogenesis of neurodevelopmental disorders affecting dendritic spine morphology, and thus excitatory synapse structure and function

MeCP2 Regulates the Synaptic Expression of a Dysbindin-BLOC-1 Network Component in Mouse Brain and Human Induced Pluripotent Stem Cell-Derived Neurons

Clinical, epidemiological, and genetic evidence suggest overlapping pathogenic mechanisms between autism spectrum disorder (ASD) and schizophrenia. We tested this hypothesis by asking if mutations in the ASD gene MECP2 which cause Rett syndrome affect the expression of genes encoding the schizophrenia risk factor dysbindin, a subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), and associated interacting proteins. We measured mRNA and protein levels of key components of a dysbindin interaction network by, quantitative real time PCR and quantitative immunohistochemistry in hippocampal samples of wild-type and Mecp2 mutant mice. In addition, we confirmed results by performing immunohistochemistry of normal human hippocampus and quantitative qRT-PCR of human inducible pluripotent stem cells (iPSCs)-derived human neurons from Rett syndrome patients. We defined the distribution of the BLOC-1 subunit pallidin in human and mouse hippocampus and contrasted this distribution with that of symptomatic Mecp2 mutant mice. Neurons from mutant mice and Rett syndrome patients displayed selectively reduced levels of pallidin transcript. Pallidin immunoreactivity decreased in the hippocampus of symptomatic Mecp2 mutant mice, a feature most prominent at asymmetric synapses as determined by immunoelectron microcopy. Pallidin immunoreactivity decreased concomitantly with reduced BDNF content in the hippocampus of Mecp2 mice. Similarly, BDNF content was reduced in the hippocampus of BLOC-1 deficient mice suggesting that genetic defects in BLOC-1 are upstream of the BDNF phenotype in Mecp2 deficient mice. Our results demonstrate that the ASD-related gene Mecp2 regulates the expression of components belonging to the dysbindin interactome and these molecular differences may contribute to synaptic phenotypes that characterize Mecp2 deficiencies and ASD.Fil: Larimore, Jennifer. Agnes Scott College; Estados UnidosFil: Ryder, Pearl V.. University of Emory; Estados UnidosFil: Kim, Kun Yong. University of Yale. School of Medicine; Estados UnidosFil: Ambrose, L. Alex. Agnes Scott College; Estados UnidosFil: Chapleau, Christopher. University Of Alabama; Estados UnidosFil: Calfa, Gaston Diego. University Of Alabama; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gross, Christina. University of Emory; Estados UnidosFil: Bassell, Gary J.. University of Emory; Estados UnidosFil: Pozzo Miller, Lucas. University Of Alabama; Estados UnidosFil: Smith, Yoland. University of Emory; Estados UnidosFil: Talbot, Konrad. The Pennsylvania State University; Estados UnidosFil: Park, In Hyun. University of Yale. School of Medicine; Estados UnidosFil: Faundez, Victor. University of Emory; Estados Unido

Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism

The process of axonal and dendritic development establishes the synaptic circuitry of the central nervous system (CNS) and is the result of interactions between intrinsic molecular factors and the external environment. One growth factor that has a compelling function in neuronal development is the neurotrophin brain-derived neurotrophic factor (BDNF). BDNF participates in axonal and dendritic differentiation during embryonic stages of neuronal development, as well as in the formation and maturation of dendritic spines during postnatal development. Recent studies have also implicated vesicular trafficking of BDNF via secretory vesicles, and both secretory and endosomal trafficking of vesicles containing synaptic proteins, such as neurotransmitter and neurotrophin receptors, in the regulation of axonal and dendritic differentiation, and in dendritic spine morphogenesis. Several genes that are either mutated or deregulated in neurodevelopmental disorders associated with mental retardation have now been identified, and several mouse models of these disorders have been generated and characterized. Interestingly, abnormalities in dendritic and synaptic structure are consistently observed in human neurodevelopmental disorders associated with mental retardation, and in mouse models of these disorders as well. Abnormalities in dendritic and synaptic differentiation are thought to underlie altered synaptic function and network connectivity, thus contributing to the clinical outcome. Here, we review the roles of BDNF and vesicular trafficking in axonal and dendritic differentiation in the context of dendritic and axonal morphological impairments commonly observed in neurodevelopmental disorders associated with mental retardation

Les entreprises para-privées de coercition : de nouveaux mercenaires ?

Comment analyser et nommer les entreprises qui « vendent de la sécurité », au-delà du gardiennage et de la sécurité de la propriété privée des individus ? Comment comprendre le phénomène de la « privatisation » de certaines fonctions dites régaliennes concernant les activités de police, de renseignement, de contrôle des personnes aux frontières, de vente d’armes, de conseil en stratégie et opérations « anti-subversives »? Ce numéro de Cultures & Conflits vise à discuter et à renouveler le débat en cours en montrant les apories des discours de légitimation des pratiques de certaines de ces entreprises qui essaient de se fondre dans un continuum d’entreprises de « protection » en banalisant leurs activités comme si aider et porter la guerre à l’étranger était dans la suite logique de la pose d’une porte blindée par un particulier effrayé, à tort ou à raison, par ce qu’il croit être la montée du crime. L’axe central de ce numéro est de faire resurgir un certain nombre de questions passées sous silence par le faux débat sur "quel est le meilleur et le plus légitime acteur en matière de coercition et de sécurité internationale : l’Etat ou le marché ?" Mais, quelle est donc la socialisation des membres du personnel des entreprises de coercition para-privée ? Comment étudier la stratégie de délégation contrôlée des gouvernements à ces entreprises para-privées qui leur permettent d’envoyer des forces sans le déclarer, ou d’augmenter les contingents dans certains domaines ou certains territoires qui sont plus illégitimes ou plus dangereux que d’autres ? C'est à ces questions, entre autres, que les auteurs de ce numéro, issus d'horizons professionnels divers, tentent de répondre en posant les jalons d'une analyse renouvelée de ce que l'on pourrait appeler les formes contemporaines du mercenariat. How can one analyse firms that claim to « sell security » in ways that go far beyond the mere guarding of individuals and the provision of security for private property ? How to understand the phenomenon of the « privatisation » of « state-functions » concerning policing, intelligence-gathering, the selling of arms, border-control, and advising and counselling in matters of strategy and « counter-insurgency operations » ? The aim of this issue of Cultures & Conflicts is to discuss and renew the ongoing debate on private military companies by showing the aporias of the discourses of legitimation relative to the practices of some of these companies. These companies often try to hide behind a undifferentiated continuum of protection provision. This allows them to present their activities as commonplace, as if there could be a logical connection between the waging of war in distant theatres and the installation of an armoured door for an individual frightened by what he believes to be an increase in petty crime. The central preoccupation of this issue is to raise a set of questions silenced by the false debate on « what is the most efficient and the most legitimate actor as far as coercion and international security is concerned : the state or the market ? » What is the pedigree of the personnel of para-private companies of coercion ? How can one study the strategy of controlled delegation of government functions to private companies, which allows the former to project forces without any democratic control or to increase troops in territories and sectors that are more illegitimate or more dangerous than others. It is these questions, as well as others, that the authors try to answer by trying to make a contribution to a renewed analysis of what could be called the contemporary forms of private soldiering