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1.
Endocrinology ; 165(7)2024 May 27.
Article in English | MEDLINE | ID: mdl-38815068

ABSTRACT

The growth hormone secretagogue receptor (GHSR), primarily known as the receptor for the hunger hormone ghrelin, potently controls food intake, yet the specific Ghsr-expressing cells mediating the orexigenic effects of this receptor remain incompletely characterized. Since Ghsr is expressed in gamma-aminobutyric acid (GABA)-producing neurons, we sought to investigate whether the selective expression of Ghsr in a subset of GABA neurons is sufficient to mediate GHSR's effects on feeding. First, we crossed mice that express a tamoxifen-dependent Cre recombinase in the subset of GABA neurons that express glutamic acid decarboxylase 2 (Gad2) enzyme (Gad2-CreER mice) with reporter mice, and found that ghrelin mainly targets a subset of Gad2-expressing neurons located in the hypothalamic arcuate nucleus (ARH) and that is predominantly segregated from Agouti-related protein (AgRP)-expressing neurons. Analysis of various single-cell RNA-sequencing datasets further corroborated that the primary subset of cells coexpressing Gad2 and Ghsr in the mouse brain are non-AgRP ARH neurons. Next, we crossed Gad2-CreER mice with reactivable GHSR-deficient mice to generate mice expressing Ghsr only in Gad2-expressing neurons (Gad2-GHSR mice). We found that ghrelin treatment induced the expression of the marker of transcriptional activation c-Fos in the ARH of Gad2-GHSR mice, yet failed to induce food intake. In contrast, food deprivation-induced refeeding was higher in Gad2-GHSR mice than in GHSR-deficient mice and similar to wild-type mice, suggesting that ghrelin-independent roles of GHSR in a subset of GABA neurons is sufficient for eliciting full compensatory hyperphagia in mice.


Subject(s)
Arcuate Nucleus of Hypothalamus , Food Deprivation , GABAergic Neurons , Ghrelin , Glutamate Decarboxylase , Hyperphagia , Receptors, Ghrelin , Animals , Male , Mice , GABAergic Neurons/metabolism , Receptors, Ghrelin/genetics , Receptors, Ghrelin/metabolism , Hyperphagia/metabolism , Ghrelin/metabolism , Ghrelin/pharmacology , Arcuate Nucleus of Hypothalamus/metabolism , Food Deprivation/physiology , Glutamate Decarboxylase/metabolism , Glutamate Decarboxylase/genetics , Mice, Transgenic , Agouti-Related Protein/metabolism , Agouti-Related Protein/genetics , Mice, Inbred C57BL
2.
Development ; 147(14)2020 07 22.
Article in English | MEDLINE | ID: mdl-32586977

ABSTRACT

Cortical interneurons (CINs) originate in the ganglionic eminences (GEs) and migrate tangentially to the cortex guided by different attractive and repulsive cues. Once inside the cortex, the cellular and molecular mechanisms determining the migration of CINs along the rostrocaudal axis are less well understood. Here, we investigated the cortical distribution of CINs originating in the medial and caudal GEs at different time points. Using molecular and genetic labeling, we showed that, in the mouse, early- and late-born CINs (E12 versus E15) are differentially distributed along the rostrocaudal axis. Specifically, late-born CINs are preferentially enriched in cortical areas closer to their respective sites of origin in the medial or caudal GE. Surprisingly, our in vitro experiments failed to show a preferential migration pattern along the rostrocaudal axis for medial- or caudal-born CINs. Moreover, in utero transplantation experiments suggested that the rostrocaudal dispersion of CINs depends on the developmental stage of the host brain and is limited by the migration time and the increasing size of the developing brain. These data suggest that the embryonic expansion of the cortex contributes to the rostrocaudal distribution of CINs.


Subject(s)
Brain/growth & development , Cerebral Cortex/cytology , GABAergic Neurons/cytology , Animals , Brain/embryology , Brain/physiology , Cell Lineage , Cell Movement , Cerebral Cortex/embryology , Cerebral Cortex/metabolism , Embryo, Mammalian/cytology , Embryo, Mammalian/metabolism , GABAergic Neurons/metabolism , Mice , Mice, Knockout , Organ Size , Somatosensory Cortex/cytology , Somatosensory Cortex/embryology , Somatosensory Cortex/metabolism , Thyroid Nuclear Factor 1/deficiency , Thyroid Nuclear Factor 1/genetics , Thyroid Nuclear Factor 1/metabolism , gamma-Aminobutyric Acid/metabolism
3.
Cell Rep ; 26(5): 1157-1173.e5, 2019 01 29.
Article in English | MEDLINE | ID: mdl-30699346

ABSTRACT

Mafb and c-Maf transcription factor (TF) expression is enriched in medial ganglionic eminence (MGE) lineages, beginning in late-secondary progenitors and continuing into mature parvalbumin (PV+) and somatostatin (SST+) interneurons. However, the functions of Maf TFs in MGE development remain to be elucidated. Herein, Mafb and c-Maf were conditionally deleted, alone and together, in the MGE and its lineages. Analyses of Maf mutant mice revealed redundant functions of Mafb and c-Maf in secondary MGE progenitors, where they repress the generation of SST+ cortical and hippocampal interneurons. By contrast, Mafb and c-Maf have distinct roles in postnatal cortical interneuron (CIN) morphological maturation, synaptogenesis, and cortical circuit integration. Thus, Mafb and c-Maf have redundant and opposing functions at different steps in CIN development.


Subject(s)
Cell Lineage , Cerebral Cortex/metabolism , Interneurons/metabolism , MafB Transcription Factor/metabolism , Proto-Oncogene Proteins c-maf/metabolism , Action Potentials , Animals , Animals, Newborn , Apoptosis , Cell Membrane/metabolism , Cell Movement , Cell Proliferation , Hippocampus/metabolism , Median Eminence/metabolism , Mice, Knockout , Neurites/metabolism , Neurogenesis , Parvalbumins/metabolism , Somatostatin/metabolism , Synapses/metabolism
4.
Cell ; 172(3): 491-499.e15, 2018 01 25.
Article in English | MEDLINE | ID: mdl-29358049

ABSTRACT

Non-coding "ultraconserved" regions containing hundreds of consecutive bases of perfect sequence conservation across mammalian genomes can function as distant-acting enhancers. However, initial deletion studies in mice revealed that loss of such extraordinarily constrained sequences had no immediate impact on viability. Here, we show that ultraconserved enhancers are required for normal development. Focusing on some of the longest ultraconserved sites genome wide, located near the essential neuronal transcription factor Arx, we used genome editing to create an expanded series of knockout mice lacking individual or combinations of ultraconserved enhancers. Mice with single or pairwise deletions of ultraconserved enhancers were viable and fertile but in nearly all cases showed neurological or growth abnormalities, including substantial alterations of neuron populations and structural brain defects. Our results demonstrate the functional importance of ultraconserved enhancers and indicate that remarkably strong sequence conservation likely results from fitness deficits that appear subtle in a laboratory setting.


Subject(s)
Conserved Sequence , Embryonic Development/genetics , Enhancer Elements, Genetic , Animals , Brain/abnormalities , Brain/embryology , Brain/metabolism , Female , Gene Deletion , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Male , Mice , Transcription Factors/genetics , Transcription Factors/metabolism
5.
Cereb Cortex ; 28(11): 3797-3815, 2018 11 01.
Article in English | MEDLINE | ID: mdl-29028947

ABSTRACT

The postnatal functions of the Dlx1&2 transcription factors in cortical interneurons (CINs) are unknown. Here, using conditional Dlx1, Dlx2, and Dlx1&2 knockouts (CKOs), we defined their roles in specific CINs. The CKOs had dendritic, synaptic, and survival defects, affecting even PV+ CINs. We provide evidence that DLX2 directly drives Gad1, Gad2, and Vgat expression, and show that mutants had reduced mIPSC amplitude. In addition, the mutants formed fewer GABAergic synapses on excitatory neurons and had reduced mIPSC frequency. Furthermore, Dlx1/2 CKO had hypoplastic dendrites, fewer excitatory synapses, and reduced excitatory input. We provide evidence that some of these phenotypes were due to reduced expression of GRIN2B (a subunit of the NMDA receptor), a high confidence Autism gene. Thus, Dlx1&2 coordinate key components of CIN postnatal development by promoting their excitability, inhibitory output, and survival.


Subject(s)
Cerebral Cortex/growth & development , GABAergic Neurons/physiology , Homeodomain Proteins/physiology , Interneurons/physiology , Synapses/physiology , Transcription Factors/physiology , gamma-Aminobutyric Acid/biosynthesis , Animals , Cerebral Cortex/cytology , Female , GABAergic Neurons/cytology , Gene Expression Regulation, Developmental , Glutamate Decarboxylase/metabolism , Homeodomain Proteins/genetics , Interneurons/cytology , Male , Mice, Knockout , Miniature Postsynaptic Potentials , Transcription Factors/genetics , Vesicular Inhibitory Amino Acid Transport Proteins/metabolism
6.
Neuron ; 84(5): 940-53, 2014 Dec 03.
Article in English | MEDLINE | ID: mdl-25467980

ABSTRACT

Little is known about genetic mechanisms that regulate the ratio of cortical excitatory and inhibitory neurons. We show that NPAS1 and NPAS3 transcription factors (TFs) are expressed in progenitor domains of the mouse basal ganglia (subpallium, MGE, and CGE). NPAS1(-/-) mutants had increased proliferation, ERK signaling, and expression of Arx in the MGE and CGE. NPAS1(-/-) mutants also had increased neocortical inhibition (sIPSC and mIPSC) and generated an excess of somatostatin(+) (SST) (MGE-derived) and vasoactive intestinal polypeptide(+) (VIP) (CGE-derived) neocortical interneurons, but had a normal density of parvalbumin(+) (PV) (MGE-derived) interneurons. In contrast, NPAS3(-/-) mutants showed decreased proliferation and ERK signaling in progenitors of the ganglionic eminences and had fewer SST(+) and VIP(+) interneurons. NPAS1 repressed activity of an Arx enhancer, and Arx overexpression resulted in increased proliferation of CGE progenitors. These results provide insights into genetic regulation of cortical interneuron numbers and cortical inhibitory tone.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Cerebral Cortex/cytology , Gene Expression Regulation, Developmental/physiology , Interneurons/classification , Interneurons/physiology , Nerve Tissue Proteins/metabolism , Age Factors , Animals , Animals, Newborn , Autistic Disorder/genetics , Autistic Disorder/pathology , Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Proliferation/genetics , Cells, Cultured , Cerebral Cortex/embryology , Cerebral Cortex/growth & development , Embryo, Mammalian , Female , Gene Expression Regulation, Developmental/genetics , Glutamate Decarboxylase/genetics , Glutamate Decarboxylase/metabolism , Humans , LIM-Homeodomain Proteins/genetics , LIM-Homeodomain Proteins/metabolism , MAP Kinase Signaling System/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Tissue Proteins/genetics , Polymorphism, Single Nucleotide/genetics , Transcription Factors/genetics , Transcription Factors/metabolism
7.
Farm Hosp ; 38(6): 454-60, 2014 Nov 03.
Article in Spanish | MEDLINE | ID: mdl-25542655

ABSTRACT

PURPOSE: Analyze the impact of economic and social crisis in volume and funding of clinical trials (CT) and observational studies (ES) from the activity of an Research Ethics Committee (REC). METHOD: REC memories 2003-2012 were reviewed. Financing of evaluated projects, CT and OS were analyzed classifying them into four groups: 1) promoted by pharmaceutical industry, 2) by scientific societies with industry support, 3) by scientific societies with government support and 4) unfunding.Two periods were compared: pre-crisis (2003-2007) and crisis (2008-2012). RESULTS: During 10 studied years, 744 protocols were evaluated: a 71% of group 1, a 9% of group 2, a 3% of group 3 and a 17% was no funding. Regarding OS, 40%, 5,4%, 8,6% and 46% were the groups 1, 2, 3 and 4 respectively. Analyzing crisis versus pre-crisis period, statistically significant differences were observed in the decreasing of number of CT phase 2 and 3 and in the rising EO. Comparing crisis related to the pre-crisis period, the Group 4 increased statistically significantly. CONCLUSIONS: Evolution of total number of studies evaluated by REC tends to be maintained and even increased over time. REC maintains its activity and even increased at the expense of financing and unfunded OS.


Objetivos: Analizar el impacto de la crisis económico-social en volumen y financiación de los ensayos clínicos (EC) y estudios observacionales (EO) a partir de la actividad de un Comité Ético de Investigación Clínica (CEIC). Método: Se revisaron las memorias del CEIC desde 2003 hasta 2012. Se analizó la financiación de los EC y los EO clasificándolos en cuatro grupos: 1) promovidos por la industria farmacéutica, 2) por sociedades científicas con soporte de la industria, 3) por sociedades apoyadas por las administraciones públicas y 4) sin financiación. Se compararon dos períodos: precrisis (2003- 2007) y crisis (2008-2012). Resultados: Se evaluaron 744 protocolos: un 71% del grupo 1, un 9% del grupo 2, un 3% del grupo 3 y un 17% carecía de financiación. En cuanto a los EO, un 40%, un 5,4%, un 8,6% y un 46% correspondían a los grupos 1, 2, 3 y 4 respectivamente. Analizando periodo crisis versus precrisis, se observaron diferencias estadísticamente significativas en el número de los EC de fase 2 y fase 3 que disminuyeron y en los EO que aumentaron. En el periodo crisis respecto al precrisis, el Grupo 4 aumentó de manera estadísticamente significativa. Conclusiones: La evolución del número total de estudios evaluados por el CEIC tiende a mantenerse e incluso incrementarse en el tiempo. El CEIC mantiene su actividad e incluso la incrementa, a expensas de EO con y sin financiación.


Subject(s)
Clinical Trials as Topic/economics , Economic Recession , Ethics Committees, Research/economics , Ethics Committees, Research/trends , Research Support as Topic/trends , Biomedical Research , Drug Industry/economics , Humans , Observational Studies as Topic/economics , Societies, Scientific , Spain
8.
Farm. hosp ; 38(6): 454-460, nov.-dic. 2014. tab, graf
Article in Spanish | IBECS | ID: ibc-133178

ABSTRACT

Objetivos: Analizar el impacto de la crisis económico-social en volumen y financiación de los ensayos clínicos (EC) y estudios observacionales (EO) a partir de la actividad de un Comité Ético de Investigación Clínica (CEIC). Método: Se revisaron las memorias del CEIC desde 2003 hasta 2012. Se analizó la financiación de los EC y los EO clasificándolos en cuatro grupos: 1) promovidos por la industria farmacéutica, 2) por sociedades científicas con soporte de la industria, 3) por sociedades apoyadas por las administraciones públicas y 4) sin financiación. Se compararon dos períodos: precrisis (2003-2007) y crisis (2008-2012). Resultados: Se evaluaron 744 protocolos: un 71% del grupo1, un 9% del grupo 2, un 3% del grupo 3 y un 17% carecía de financiación. En cuanto a los EO, un 40%, un 5,4%,un 8,6% y un 46% correspondían a los grupos 1, 2, 3 y 4respectivamente. Analizando periodo crisis versus precrisis, se observaron diferencias estadísticamente significativas en el número de los EC de fase 2 y fase 3 que disminuyeron y en los EO que aumentaron. En el periodo crisis respecto al precrisis, el Grupo 4 aumentó de manera estadísticamente significativa. Conclusiones: La evolución del número total de estudios evaluados por el CEIC tiende a mantenerse e incluso incrementarse en el tiempo. El CEIC mantiene su actividad e incluso la incrementa, a expensas de EO con y sin financiación (AU)


Purpose: Analyse the impact of economic and social crisis in volume and funding of clinical trials (CT) and observational studies(ES) from the activity of an Research Ethics Committee (REC). Method: REC memories 2003-2012 were reviewed. Financing of evaluated projects, CT and OS were analyzed classifying them into four groups: 1) promoted by pharmaceutical industry, 2) by scientific societies with industry support, 3) by scientific societies with government support and 4) unfunding. Two periods were compared: pre-crisis (2003-2007) and crisis (2008-2012). Results: During 10 studied years, 744 protocols were evaluated: a 71% of group 1, a 9% of group 2, a 3% of group 3 and a 17% was no funding. Regarding OS, 40%, 5,4%, 8,6% and 46% were the groups 1, 2, 3 and 4 respectively. Analyzing crisis versus pre-crisis period, statistically significant differences were observed in the decreasing of number of CT phase 2 and 3 and in the rising EO. Comparing crisis related to the pre-crisis period, the Group 4 increased statistically significantly. Conclusions: Evolution of total number of studies evaluated by REC tends to be maintained and even increased over time. REC maintains its activity and even increased at the expense of financing and unfunded OS (AU)


Subject(s)
Humans , Ethics Committees, Research/organization & administration , Clinical Trials as Topic/economics , Research Financing , Economic Recession , Biomedical Research/economics
9.
J Comp Neurol ; 521(7): 1561-84, 2013 May 01.
Article in English | MEDLINE | ID: mdl-23042297

ABSTRACT

Mice lacking the Dlx1 and Dlx2 homeobox genes (Dlx1/2 mutants) have severe deficits in subpallial differentiation, including overexpression of the Gsx1 and Gsx2 homeobox genes. To investigate whether Gsx overexpression contributes to the Dlx1/2 mutant phenotypes, we made compound loss-of-function mutants. Eliminating Gsx2 function from the Dlx1/2 mutants rescued the increased expression of Ascl1 and Hes5 (Notch signaling mediators) and Olig2 (oligodendrogenesis mediator). In addition, Dlx1/2;Gsx2 mutants, like Dlx1/2;Ascl1 mutants, exacerbated the Gsx2 and Dlx1/2 patterning and differentiation phenotypes, particularly in the lateral ganglionic eminence (LGE) caudal ganglionic eminence (CGE), and septum, including loss of GAD1 expression. On the other hand, eliminating Gsx1 function from the Dlx1/2 mutants (Dlx1/2;Gsx1 mutants) did not severely exacerbate their phenotype; on the contrary, it resulted in a partial rescue of medial ganglionic eminence (MGE) properties, including interneuron migration to the cortex. Thus, despite their redundant properties, Gsx1 and -2 have distinct interactions with Dlx1 and -2. Gsx2 interaction is strongest in the LGE, CGE, and septum, whereas the Gsx1 interaction is strongest in the MGE. From these studies, and earlier studies, we present a model of the transcriptional network that regulates early steps of subcortical development.


Subject(s)
Brain/physiology , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Neurogenesis/physiology , Transcription Factors/genetics , Animals , Brain/embryology , Embryo, Mammalian , Fluorescent Antibody Technique , In Situ Hybridization , Mice , Mice, Mutant Strains , Phenotype
10.
Neuron ; 76(2): 338-52, 2012 Oct 18.
Article in English | MEDLINE | ID: mdl-23083737

ABSTRACT

Neurogenesis relies on a delicate balance between progenitor maintenance and neuronal production. Progenitors divide symmetrically to increase the pool of dividing cells. Subsequently, they divide asymmetrically to self-renew and produce new neurons or, in some brain regions, intermediate progenitor cells (IPCs). Here we report that central nervous system progenitors express Robo1 and Robo2, receptors for Slit proteins that regulate axon guidance, and that absence of these receptors or their ligands leads to loss of ventricular mitoses. Conversely, production of IPCs is enhanced in Robo1/2 and Slit1/2 mutants, suggesting that Slit/Robo signaling modulates the transition between primary and intermediate progenitors. Unexpectedly, these defects do not lead to transient overproduction of neurons, probably because supernumerary IPCs fail to detach from the ventricular lining and cycle very slowly. At the molecular level, the role of Slit/Robo in progenitor cells involves transcriptional activation of the Notch effector Hes1. These findings demonstrate that Robo signaling modulates progenitor cell dynamics in the developing brain.


Subject(s)
Cell Proliferation , Central Nervous System/cytology , Intercellular Signaling Peptides and Proteins/metabolism , Nerve Tissue Proteins/metabolism , Receptors, Immunologic/metabolism , Signal Transduction/physiology , Stem Cells/physiology , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cadherins/metabolism , Cell Count , Cell Cycle/genetics , Cells, Cultured , Central Nervous System/embryology , Chi-Square Distribution , Embryo, Mammalian , Gene Expression Regulation, Developmental/genetics , Green Fluorescent Proteins/genetics , Homeodomain Proteins/metabolism , Intercellular Signaling Peptides and Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation/genetics , Neocortex/cytology , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Neurogenesis , Neurons/physiology , Receptors, Immunologic/deficiency , Signal Transduction/genetics , Transcription Factor HES-1 , Transfection , Roundabout Proteins
11.
J Neurosci ; 31(46): 16570-80, 2011 Nov 16.
Article in English | MEDLINE | ID: mdl-22090484

ABSTRACT

GABA-containing (GABAergic) interneurons comprise a very heterogeneous group of cells that are crucial for cortical function. Different classes of interneurons specialize in targeting specific subcellular domains of excitatory pyramidal cells or other interneurons, which provides cortical circuits with an enormous capability for information processing. As in other regions of the CNS, cortical interneuron diversity is thought to emerge from the genetic specification of different groups of progenitor cells within the subpallium. Most cortical interneurons originate from two main regions, the medial and the caudal ganglionic eminences (MGE and CGE, respectively). In addition, it has been shown that progenitors in the embryonic preoptic area (POA) also produce a small population of cortical GABAergic interneurons. Here, we show that the contribution of the POA to the complement of cortical GABAergic interneurons is larger than previously believed. Using genetic fate mapping and in utero transplantation experiments, we demonstrate that Dbx1-expressing progenitor cells in the POA give rise to a small but highly diverse cohort of cortical interneurons, with some neurochemical and electrophysiological characteristics that were previously attributed to MGE- or CGE-derived interneurons. There are, however, some features that seem to distinguish POA-derived interneurons from MGE- or CGE-derived cells, such as their preferential laminar location. These results indicate that the mechanisms controlling the specification of different classes of cortical interneurons might be more complex than previously expected. Together with earlier findings, our results also suggest that the POA generates nearly 10% of the GABAergic interneurons in the cerebral cortex of the mouse.


Subject(s)
Interneurons/physiology , Neural Stem Cells/physiology , Preoptic Area/cytology , Preoptic Area/embryology , Somatosensory Cortex/cytology , gamma-Aminobutyric Acid/metabolism , Animals , Animals, Newborn , Bacterial Proteins/genetics , Bromodeoxyuridine/metabolism , Cell Movement/genetics , Electric Stimulation , Embryo, Mammalian , Gene Expression Regulation, Developmental/genetics , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Homeodomain Proteins/genetics , In Vitro Techniques , Indoles/metabolism , Luminescent Proteins/genetics , Membrane Potentials/drug effects , Membrane Potentials/genetics , Mice , Mice, Transgenic , Nerve Tissue Proteins/metabolism , Neural Stem Cells/metabolism , Neural Stem Cells/transplantation , Patch-Clamp Techniques , Preoptic Area/metabolism , Proteins/genetics , RNA, Untranslated , Somatosensory Cortex/growth & development
12.
Neuron ; 69(1): 77-90, 2011 Jan 13.
Article in English | MEDLINE | ID: mdl-21220100

ABSTRACT

The chemokine Cxcl12 binds Cxcr4 and Cxcr7 receptors to control cell migration in multiple biological contexts, including brain development, leukocyte trafficking, and tumorigenesis. Both receptors are expressed in the CNS, but how they cooperate during migration has not been elucidated. Here, we used the migration of cortical interneurons as a model to study this process. We found that Cxcr4 and Cxcr7 are coexpressed in migrating interneurons, and that Cxcr7 is essential for chemokine signaling. Intriguingly, this process does not exclusively involve Cxcr7, but most critically the modulation of Cxcr4 function. Thus, Cxcr7 is necessary to regulate Cxcr4 protein levels, thereby adapting chemokine responsiveness in migrating cells. This demonstrates that a chemokine receptor modulates the function of another chemokine receptor by controlling the amount of protein that is made available for signaling at the cell surface.


Subject(s)
Cell Movement/physiology , Chemokine CXCL12/metabolism , Interneurons/metabolism , Receptors, CXCR4/metabolism , Receptors, CXCR/metabolism , Signal Transduction/physiology , Animals , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/growth & development , Immunohistochemistry , In Situ Hybridization , Interneurons/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, CXCR/genetics , Receptors, CXCR4/genetics
13.
Nature ; 464(7293): 1376-80, 2010 Apr 29.
Article in English | MEDLINE | ID: mdl-20393464

ABSTRACT

Schizophrenia is a complex disorder that interferes with the function of several brain systems required for cognition and normal social behaviour. Although the most notable clinical aspects of the disease only become apparent during late adolescence or early adulthood, many lines of evidence suggest that schizophrenia is a neurodevelopmental disorder with a strong genetic component. Several independent studies have identified neuregulin 1 (NRG1) and its receptor ERBB4 as important risk genes for schizophrenia, although their precise role in the disease process remains unknown. Here we show that Nrg1 and ErbB4 signalling controls the development of inhibitory circuitries in the mammalian cerebral cortex by cell-autonomously regulating the connectivity of specific GABA (gamma-aminobutyric acid)-containing interneurons. In contrast to the prevalent view, which supports a role for these genes in the formation and function of excitatory synapses between pyramidal cells, we found that ErbB4 expression in the mouse neocortex and hippocampus is largely confined to certain classes of interneurons. In particular, ErbB4 is expressed by many parvalbumin-expressing chandelier and basket cells, where it localizes to axon terminals and postsynaptic densities receiving glutamatergic input. Gain- and loss-of-function experiments, both in vitro and in vivo, demonstrate that ErbB4 cell-autonomously promotes the formation of axo-axonic inhibitory synapses over pyramidal cells, and that this function is probably mediated by Nrg1. In addition, ErbB4 expression in GABA-containing interneurons regulates the formation of excitatory synapses onto the dendrites of these cells. By contrast, ErbB4 is dispensable for excitatory transmission between pyramidal neurons. Altogether, our results indicate that Nrg1 and ErbB4 signalling is required for the wiring of GABA-mediated circuits in the postnatal cortex, providing a new perspective to the involvement of these genes in the aetiology of schizophrenia.


Subject(s)
Cerebral Cortex/metabolism , ErbB Receptors/metabolism , Interneurons/metabolism , Neural Pathways/physiology , Neuregulin-1/metabolism , Signal Transduction , gamma-Aminobutyric Acid/metabolism , Animals , Cell Differentiation , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Cerebral Cortex/growth & development , Dendrites/metabolism , Embryo, Mammalian , ErbB Receptors/deficiency , ErbB Receptors/genetics , Excitatory Postsynaptic Potentials/genetics , Excitatory Postsynaptic Potentials/physiology , Female , In Vitro Techniques , Mice , Neural Inhibition/genetics , Neural Inhibition/physiology , Pyramidal Cells/metabolism , Receptor, ErbB-4 , Schizophrenia/genetics , Schizophrenia/metabolism , Synapses/metabolism
14.
J Neurosci ; 30(8): 2824-34, 2010 Feb 24.
Article in English | MEDLINE | ID: mdl-20181580

ABSTRACT

The mechanisms controlling the assembly of brain nuclei are poorly understood. In the forebrain, it is typically assumed that the formation of nuclei follows a similar sequence of events that in the cortex. In this structure, projection neurons are generated sequentially from common progenitor cells and migrate radially to reach their final destination, whereas interneurons are generated remotely and arrive to the cortex through tangential migration. Using the globus pallidus as a model to study the formation of forebrain nuclei, we found that the development of this basal ganglia structure involves the generation of several distinct classes of projection neurons from relatively distant progenitor pools, which then assemble together through tangential migration. Our results thus suggest that tangential migration in the forebrain is not limited to interneurons, as previously thought, but also involves projection neurons and reveal that the assembly of forebrain nuclei is more complex than previously anticipated.


Subject(s)
Globus Pallidus/embryology , Globus Pallidus/metabolism , Neurons/metabolism , Prosencephalon/embryology , Prosencephalon/metabolism , Stem Cells/metabolism , Acetylcholine/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Biomarkers/analysis , Biomarkers/metabolism , Cell Differentiation/physiology , Cell Movement/physiology , Choline O-Acetyltransferase/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gene Expression Regulation, Developmental/physiology , Globus Pallidus/cytology , Mice , Mice, Knockout , Mice, Transgenic , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neural Pathways/cytology , Neural Pathways/embryology , Neural Pathways/metabolism , Neurogenesis/physiology , Neurons/cytology , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Parvalbumins/metabolism , Prosencephalon/cytology , Stem Cells/cytology , Thyroid Nuclear Factor 1 , Transcription Factors/genetics , Transcription Factors/metabolism , gamma-Aminobutyric Acid/metabolism
15.
Drug News Perspect ; 22(6): 325-39, 2009.
Article in English | MEDLINE | ID: mdl-19771322

ABSTRACT

A clinical investigation program was carried out to replace endogenous albumin of patients with mild to moderate Alzheimer's disease (AD) with 5% Human Albumin Grifols(R) through a plasma exchange (PE) schedule, in order to alter the dynamic equilibrium between albumin-bound Abeta in plasma and Abeta in cerebrospinal fluid. In a pilot proof-of-concept study, 7 patients underwent 6 PE in 3 weeks and 1 year of follow-up. Plasma Abeta determinations demonstrated a variation pattern in levels in relation with the PEs. Cognitive status scores (MMSE and ADAS-Cog) were more stable than expected. In a phase II clinical trial, 29 patients were randomized into PEtreated and control groups with 1 year follow-up. Interim results point toward the occurrence of Abeta40 mobilization in the PE-treated patients, who scored better in cognitive tests (differences at 9 months: 2.5 in MMSE and 5.5 in ADAS-cog). These results suggest that a PE program with 5% Human Albumin Grifols may have a promising role in the treatment of mild to moderate AD.


Subject(s)
Alzheimer Disease/therapy , Plasma Exchange/methods , Serum Albumin/administration & dosage , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Animals , Clinical Trials as Topic , Cognition Disorders/etiology , Cognition Disorders/therapy , Drug Delivery Systems , Humans , Serum Albumin/metabolism
16.
Transfus Apher Sci ; 39(2): 115-21, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18710822

ABSTRACT

Thirty-six fresh frozen plasma (FFP) units obtained from whole blood donations were used for 12 replicate experiments. For each replicate experiment, three ABO-matched FFP units were pooled and divided into three units containing different volumes of identical plasma. One unit was used as control FFP, one unit was treated with methylene blue plus visible light and one unit was treated with amotosalen and UVA light. The overall coagulation factor levels were better maintained in untreated FFP than in photochemically treated plasma. However, treated-plasma by both photochemical methods maintained coagulation factor levels that met or exceeded the European Pharmacopeia requirements for therapeutic plasma.


Subject(s)
Blood Proteins/analysis , Methylene Blue/pharmacology , Plasma/chemistry , Virus Inactivation , Blood Coagulation Factors/analysis , Blood-Borne Pathogens/radiation effects , Fibrinogen/analysis , Furocoumarins/pharmacology , Furocoumarins/radiation effects , Humans , Light , Methylene Blue/radiation effects , Photochemistry , Plasma/drug effects , Ultraviolet Rays , von Willebrand Factor/analysis
17.
Transfusion ; 48(9): 1966-70, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18564402

ABSTRACT

BACKGROUND: The transfusion of red cell (RBC) bags with high amounts of potassium (K(+)) causes concern about an increased risk of cardiac arrest because of transient hyperkalemia. To prevent K(+) overload, a K(+) adsorption filter (PAF) is available for use at bedside. The aim of the present study was to analyze the efficacy in reducing K(+) load in irradiated RBC bags with this PAF. STUDY DESIGN AND METHODS: Whole-blood (WB) bags were collected from volunteer donors on Day 0. RBC bags were prepared from WB bags on Day +1 and stored at 2 to 6 degrees C. RBC bags were irradiated on Day +14 and filtered with the PAF on Day +28, according to the manufacturers' instructions. The plasma electrolyte levels (Na(+), K(+), Cl(-), Ca(2+), and Mg(2+)) were measured at the different points during storage. RESULTS: Twelve RBC bags were prepared with a final volume of 274 +/- 15 mL. On Day +28, the volume of RBC bags was 257 +/- 15 mL, and the PAF was used at a flow rate of 4 +/- 0.7 mL per minute. K(+) level after RBC bag preparation was 1.28 +/- 0.59 mmol per L. The K(+) level was 60.6 +/- 2.68 mmol per L on Day +28, just before filtration with the PAF. After filtration, the level of K(+) was 3.42 +/- 2.91 mmol per L. CONCLUSION: This study has shown a high efficacy in reducing potassium load in irradiated RBC bags with the use of the PAF.


Subject(s)
Erythrocyte Transfusion/instrumentation , Erythrocyte Transfusion/methods , Potassium/isolation & purification , Adsorption , Blood Donors , Filtration/instrumentation , Filtration/methods , Humans , Potassium/blood , Potassium/chemistry , Reproducibility of Results
18.
J Neurosci ; 28(7): 1613-24, 2008 Feb 13.
Article in English | MEDLINE | ID: mdl-18272682

ABSTRACT

Functioning of the cerebral cortex requires the coordinated assembly of circuits involving glutamatergic projection neurons and GABAergic interneurons. Although much is known about the migration of interneurons from the subpallium to the cortex, our understanding of the mechanisms controlling their precise integration within the cortex is still limited. Here, we have investigated in detail the behavior of GABAergic interneurons as they first enter the developing cortex by using time-lapse videomicroscopy, slice culture, and in utero experimental manipulations and analysis of mouse mutants. We found that interneurons actively avoid the cortical plate for a period of approximately 48 h after reaching the pallium; during this time, interneurons disperse tangentially through the marginal and subventricular zones. Perturbation of CXCL12/CXCR4 signaling causes premature cortical plate invasion by cortical interneurons and, in the long term, disrupts their laminar and regional distribution. These results suggest that regulation of cortical plate invasion by GABAergic interneurons is a key event in cortical development, because it directly influences the coordinated formation of appropriate glutamatergic and GABAergic neuronal assemblies.


Subject(s)
Cell Movement/physiology , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Chemokine CXCL12/metabolism , Interneurons/cytology , Interneurons/metabolism , Receptors, CXCR4/metabolism , Animals , Cell Communication , Coculture Techniques , Mice , Mice, Inbred C57BL , Mice, Transgenic , Signal Transduction , gamma-Aminobutyric Acid/metabolism
19.
J Neurosci ; 27(36): 9682-95, 2007 Sep 05.
Article in English | MEDLINE | ID: mdl-17804629

ABSTRACT

The mammalian telencephalon is considered the most complex of all biological structures. It comprises a large number of functionally and morphologically distinct types of neurons that coordinately control most aspects of cognition and behavior. The subpallium, for example, not only gives rise to multiple neuronal types that form the basal ganglia and parts of the amygdala and septum but also is the origin of an astonishing diversity of cortical interneurons. Despite our detailed knowledge on the molecular, morphological, and physiological properties of most of these neuronal populations, the mechanisms underlying their generation are still poorly understood. Here, we comprehensively analyzed the expression patterns of several transcription factors in the ventricular zone of the developing subpallium in the mouse to generate a detailed molecular map of the different progenitor domains present in this region. Our study demonstrates that the ventricular zone of the mouse subpallium contains at least 18 domains that are uniquely defined by the combinatorial expression of several transcription factors. Furthermore, the results of microtransplantation experiments in vivo corroborate that anatomically defined regions of the mouse subpallium, such as the medial ganglionic eminence, can be subdivided into functionally distinct domains.


Subject(s)
Gene Expression Regulation, Developmental/physiology , Stem Cells/physiology , Telencephalon/embryology , Transcription Factors/physiology , Animals , Brain Tissue Transplantation , Cerebral Ventricles/cytology , Cerebral Ventricles/embryology , Embryonic Development , Genes, Reporter , Green Fluorescent Proteins/genetics , Mice , Mice, Transgenic , Stem Cells/cytology , Telencephalon/cytology
20.
Transfus Apher Sci ; 36(3): 243-7, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17569593

ABSTRACT

We compared the data of our quality control laboratory of the blood components according to the blood component preparation method that we used. We prepared blood components from top and top whole blood (WB) bags and manual pooling of buffy coats (BCs) (method I) or from top and bottom WB bags and automated pooling of BCs with OrbiSac (method II). Pooled platelet concentrates (PC) obtained with method II had higher platelet content when compared with pooled PCs obtained with method I (3.5+/-0.7x10(11) vs. 2.6+/-0.8x10(11); p<0.001). The hemoglobin content in the RBCs obtained with method I was higher when compared with method II (55+/-7g vs. 52.5+/-6.6g; p<0.001).


Subject(s)
Blood Component Removal/methods , Blood , Hemoglobinometry , Hemoglobins/analysis , Humans , Methods , Quality Control
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