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1.
Clin Chem Lab Med ; 60(1): 66-73, 2022 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-34670030

RESUMEN

OBJECTIVES: Serum indices included in clinical chemistry instruments are widely used by laboratories to assess the quality of samples. Instruments that report quantitative results allow an evaluation of their diagnostic performance in a similar way to other biochemical tests. The Spanish Society of Laboratory Medicine (SEQC-ML) launched a monthly External Quality program of serum indices in 2018 using three lyophilized materials of simultaneous annual distribution. We present the results of the first three years of the program. METHODS: The use of four different quality control materials with different concentrations in three alternate months allows an annual evaluation of the participant's accuracy. Assigned values are established by consensus among homogeneous groups, considering necessary at least 10 participants for a comparison at instrument level. The average percentage difference results per instrument allow the assessment of bias among groups. RESULTS: The imprecision of the three indices ranges between 3 and 9%, with no major differences among instruments. Significant differences were observed in all indices among instruments with more than 10 participants (Roche Cobas, Abbott Architect, Abbott Alinity and Siemens Advia). The 90th percentile of the distribution of percentage differences was used as the analytical performance specification (APS). An improvement in performance was observed in the first three years of the program, probably due to the learning curve effect. In 2020, APS of 7.8, 12.2 and 9.7% were proposed for hemolytic, icteric and lipemic indices, respectively. CONCLUSIONS: Serum indices have a great impact on the quality and the reliability of laboratory test results. Participation in proficiency testing programs for serum indices is helpful to encourage harmonization among providers and laboratories.


Asunto(s)
Laboratorios , Ensayos de Aptitud de Laboratorios , Humanos , Control de Calidad , Reproducibilidad de los Resultados , Suero
2.
Epilepsy Behav ; 118: 107946, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33848848

RESUMEN

OBJECTIVE: This study was aimed to analyze the effectiveness of sodium channel blockers (SCBs) in CDKL5 deficiency disorder (CDD)-related epilepsy. METHODS: A retrospective, observational study was performed, including patients with CDD diagnosis evaluated between 2016 and 2019 at three tertiary Epilepsy Centers. Demographic, electroclinical and genetic features, as well as ASM treatments and their outcomes were analyzed, with special focus on SCBs. RESULTS: Twenty-one patients evaluated at three tertiary Epilepsy Centers were included, of which 19 presented with epilepsy (90.5%); all had pathogenic mutations of CDKL5. Six patients (31.6%) were classified as SCB responders (more than 50% reduction), four being currently seizure free (mean seizure-free period of 8 years). Most frequent SCB drugs were oxcarbazepine (OXC), carbamazepine (CBZ), and lacosamide (LCM). None of them presented relevant adverse events. In contrast, three patients showed seizure aggravation in the non-responder group. When comparing both groups, responders had statistically significant younger age at SCB treatment and epilepsy onset, higher proportion of focal epileptiform activity and less frequent history of West syndrome. CONCLUSIONS: The results of this study indicate that treatment with SCBs might be effective and safe in a subset of patients with CDD-related epilepsy.


Asunto(s)
Epilepsia , Bloqueadores de los Canales de Sodio/uso terapéutico , Espasmos Infantiles , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Síndromes Epilépticos , Humanos , Lactante , Proteínas Serina-Treonina Quinasas/genética , Estudios Retrospectivos , Espasmos Infantiles/complicaciones , Espasmos Infantiles/tratamiento farmacológico , Espasmos Infantiles/genética
3.
Cereb Cortex ; 30(11): 5667-5685, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32572460

RESUMEN

The formation of functional cortical maps in the cerebral cortex results from a timely regulated interaction between intrinsic genetic mechanisms and electrical activity. To understand how transcriptional regulation influences network activity and neuronal excitability within the neocortex, we used mice deficient for Nr2f1 (also known as COUP-TFI), a key determinant of primary somatosensory (S1) area specification during development. We found that the cortical loss of Nr2f1 impacts on spontaneous network activity and synchronization of S1 cortex at perinatal stages. In addition, we observed alterations in the intrinsic excitability and morphological features of layer V pyramidal neurons. Accordingly, we identified distinct voltage-gated ion channels regulated by Nr2f1 that might directly influence intrinsic bioelectrical properties during critical time windows of S1 cortex specification. Altogether, our data suggest a tight link between Nr2f1 and neuronal excitability in the developmental sequence that ultimately sculpts the emergence of cortical network activity within the immature neocortex.


Asunto(s)
Factor de Transcripción COUP I/metabolismo , Neurogénesis/fisiología , Células Piramidales/metabolismo , Corteza Somatosensorial/embriología , Corteza Somatosensorial/crecimiento & desarrollo , Animales , Femenino , Regulación del Desarrollo de la Expresión Génica/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Corteza Somatosensorial/metabolismo
4.
Clin Chem Lab Med ; 56(11): 1806-1818, 2018 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-29729140

RESUMEN

BACKGROUND: The stability limit of an analyte in a biological sample can be defined as the time required until a measured property acquires a bias higher than a defined specification. Many studies assessing stability and presenting recommendations of stability limits are available, but differences among them are frequent. The aim of this study was to classify and to grade a set of bibliographic studies on the stability of five common blood measurands and subsequently generate a consensus stability function. METHODS: First, a bibliographic search was made for stability studies for five analytes in blood: alanine aminotransferase (ALT), glucose, phosphorus, potassium and prostate specific antigen (PSA). The quality of every study was evaluated using an in-house grading tool. Second, the different conditions of stability were uniformly defined and the percent deviation (PD%) over time for each analyte and condition were scattered while unifying studies with similar conditions. RESULTS: From the 37 articles considered as valid, up to 130 experiments were evaluated and 629 PD% data were included (106 for ALT, 180 for glucose, 113 for phosphorus, 145 for potassium and 85 for PSA). Consensus stability equations were established for glucose, potassium, phosphorus and PSA, but not for ALT. CONCLUSIONS: Time is the main variable affecting stability in medical laboratory samples. Bibliographic studies differ in recommedations of stability limits mainly because of different specifications for maximum allowable error. Definition of a consensus stability function in specific conditions can help laboratories define stability limits using their own quality specifications.


Asunto(s)
Recolección de Muestras de Sangre/métodos , Alanina Transaminasa/sangre , Glucemia/química , Humanos , Fósforo/sangre , Potasio/sangre , Fase Preanalítica , Antígeno Prostático Específico/sangre , Estabilidad Proteica , Temperatura
5.
J Biol Chem ; 289(16): 11396-11409, 2014 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-24509844

RESUMEN

Glycine receptors (GlyRs) mediate inhibitory neurotransmission in spinal cord and brainstem. They are clustered at inhibitory postsynapses via a tight interaction of their ß subunits (GlyRß) with the scaffolding protein gephyrin. In an attempt to isolate additional proteins interacting with GlyRß, we performed pulldown experiments with rat brain extracts using a glutathione S-transferase fusion protein encompassing amino acids 378-455 of the large intracellular loop of GlyRß as bait. This identified syndapin I (SdpI) as a novel interaction partner of GlyRß that coimmunoprecipitates with native GlyRs from brainstem extracts. Both SdpI and SdpII bound efficiently to the intracellular loop of GlyRß in vitro and colocalized with GlyRß upon coexpression in COS-7 cells. The SdpI-binding site was mapped to a proline-rich sequence of 22 amino acids within the intracellular loop of GlyRß. Deletion and point mutation analysis disclosed that SdpI binding to GlyRß is Src homology 3 domain-dependent. In cultured rat spinal cord neurons, SdpI immunoreactivity was found to partially colocalize with marker proteins of inhibitory and excitatory synapses. When SdpI was acutely knocked down in cultured spinal cord neurons by viral miRNA expression, postsynaptic GlyR clusters were significantly reduced in both size and number. Similar changes in GlyR cluster properties were found in spinal cultures from SdpI-deficient mice. Our results are consistent with a role of SdpI in the trafficking and/or cytoskeletal anchoring of synaptic GlyRs.


Asunto(s)
Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Neuropéptidos/metabolismo , Fosfoproteínas/metabolismo , Receptores de Glicina/metabolismo , Médula Espinal/metabolismo , Sinapsis/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Encéfalo/citología , Células COS , Proteínas Portadoras/genética , Chlorocebus aethiops , Proteínas del Citoesqueleto , Humanos , Péptidos y Proteínas de Señalización Intracelular , Ratones , Ratones Mutantes , Neuronas/citología , Neuronas/metabolismo , Neuropéptidos/genética , Fosfoproteínas/genética , Mutación Puntual , Unión Proteica , Estructura Secundaria de Proteína , Transporte de Proteínas/fisiología , Proteómica , Ratas , Ratas Wistar , Receptores de Glicina/genética , Médula Espinal/citología , Sinapsis/genética
6.
Development ; 139(17): 3200-10, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22872087

RESUMEN

The establishment of neural circuits depends on the ability of axonal growth cones to sense their surrounding environment en route to their target. To achieve this, a coordinated rearrangement of cytoskeleton in response to extracellular cues is essential. Although previous studies have identified different chemotropic and adhesion molecules that influence axonal development, the molecular mechanism by which these signals control the cytoskeleton remains poorly understood. Here, we show that in vivo conditional ablation of the focal adhesion kinase gene (Fak) from mouse hippocampal pyramidal cells impairs axon outgrowth and growth cone morphology during development, which leads to functional defects in neuronal connectivity. Time-lapse recordings and in vitro FRAP analysis indicate that filopodia motility is altered in growth cones lacking FAK, probably owing to deficient actin turnover. We reveal the intracellular pathway that underlies this process and describe how phosphorylation of the actin nucleation-promoting factor N-WASP is required for FAK-dependent filopodia formation. Our study reveals a novel mechanism through which FAK controls filopodia formation and actin nucleation during axonal development.


Asunto(s)
Actinas/metabolismo , Axones/fisiología , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Red Nerviosa/crecimiento & desarrollo , Neuronas/citología , Seudópodos/fisiología , Animales , Axones/enzimología , Cartilla de ADN/genética , Electroporación , Potenciales Postsinápticos Excitadores/fisiología , Recuperación de Fluorescencia tras Fotoblanqueo , Proteína-Tirosina Quinasas de Adhesión Focal/genética , Conos de Crecimiento/fisiología , Inmunohistoquímica , Inmunoprecipitación , Ratones , Ratones Transgénicos , Faloidina , Seudópodos/enzimología
7.
Clin Chem Lab Med ; 51(10): 1943-9, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23612543

RESUMEN

BACKGROUND: In order to minimize the influence of glycolysis on diabetes mellitus (DM) diagnostic tests, we have compared the behavior of citric/citrate, fluoride additives and gel-serum with plasma-heparin under careful preanalytical conditions. Subsequently, we compared the effectiveness of both fluoride and citric additives at different pre-centrifugation times. Finally, the influence of citric/citrate collection tube on diagnostic tests results was evaluated. METHODS: The first study of 80 voluntary patients assessed the glucose bias of citric/citrate, fluoride additive tubes and gel-serum tubes versus plasma-heparin tubes at several medical decision cut-offs (MDC). The second study performed with 72 volunteers evaluated additives, simulating transport times to the laboratory and centrifugation delay periods. Final evaluation compares the proportion of positive tests in total tests carried out in two different periods. RESULTS: When citric/citrate (n=79) and fluoride tubes (n=60) were compared with plasma-heparin under controlled preanalytical conditions, both met the bias specification for plasma glucose (±1.8%) at seven MDC. On the contrary, serum samples (n=15) did not meet it at five MDC. In the second study, differences in glucose values at distinct pre-centrifugation times were not statistically significant for citric/citrate tubes, but significant for fluoride tubes and also for comparison of fluoride and citric/citrate tubes. Hemolysis in fluoride tubes was higher. Citric/citrate tube implementation in our laboratory caused an increase in positive diagnostic tests that were only statistically significant for gestational diabetes mellitus (GDM) screening. CONCLUSIONS: Citric/citrate additive tube is equivalent to plasma-heparin avoiding glycolysis completely and immediately under careful preanalytical conditions even with a 3-h delay in plasma separation. According to used MDC we have not statistically significantly increased the diagnoses of DM cases.


Asunto(s)
Células Sanguíneas/efectos de los fármacos , Ácido Cítrico/farmacología , Diabetes Gestacional/sangre , Diabetes Gestacional/diagnóstico , Glucólisis/efectos de los fármacos , Fluoruro de Sodio/farmacología , Adulto , Anticoagulantes/química , Células Sanguíneas/metabolismo , Células Sanguíneas/patología , Glucemia/análisis , Recolección de Muestras de Sangre/instrumentación , Recolección de Muestras de Sangre/métodos , Tampones (Química) , Centrifugación , Ácido Cítrico/química , Diabetes Gestacional/patología , Femenino , Hemólisis , Heparina/química , Humanos , Masculino , Persona de Mediana Edad , Embarazo , Fluoruro de Sodio/química
8.
Front Cell Dev Biol ; 11: 1112062, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36819097

RESUMEN

Interneurons are fundamental cells for maintaining the excitation-inhibition balance in the brain in health and disease. While interneurons have been shown to play a key role in the pathophysiology of autism spectrum disorder (ASD) in adult mice, little is known about how their maturation is altered in the developing striatum in ASD. Here, we aimed to track striatal developing interneurons and elucidate the molecular and physiological alterations in the Cntnap2 knockout mouse model. Using Stereo-seq and single-cell RNA sequencing data, we first characterized the pattern of expression of Cntnap2 in the adult brain and at embryonic stages in the medial ganglionic eminence (MGE), a transitory structure producing most cortical and striatal interneurons. We found that Cntnap2 is enriched in the striatum, compared to the cortex, particularly in the developing striatal cholinergic interneurons. We then revealed enhanced MGE-derived cell proliferation, followed by increased cell loss during the canonical window of developmental cell death in the Cntnap2 knockout mice. We uncovered specific cellular and molecular alterations in the developing Lhx6-expressing cholinergic interneurons of the striatum, which impacts interneuron firing properties during the first postnatal week. Overall, our work unveils some of the mechanisms underlying the shift in the developmental trajectory of striatal interneurons which greatly contribute to the ASD pathogenesis.

9.
Neurotherapeutics ; 20(5): 1294-1304, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37278968

RESUMEN

MOGHE is defined as mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Approximately half of the patients with histopathologically confirmed MOGHE carry a brain somatic variant in the SLC35A2 gene encoding a UDP-galactose transporter. Previous research showed that D-galactose supplementation results in clinical improvement in patients with a congenital disorder of glycosylation due to germline variants in SLC35A2. We aimed to evaluate the effects of D-galactose supplementation in patients with histopathologically confirmed MOGHE, with uncontrolled seizures or cognitive impairment and epileptiform activity at the EEG after epilepsy surgery (NCT04833322). Patients were orally supplemented with D-galactose for 6 months in doses up to 1.5 g/kg/day and monitored for seizure frequency including 24-h video-EEG recording, cognition and behavioral scores, i.e., WISC, BRIEF-2, SNAP-IV, and SCQ, and quality of life measures, before and 6 months after treatment. Global response was defined by > 50% improvement of seizure frequency and/or cognition and behavior (clinical global impression of "much improved" or better). Twelve patients (aged 5-28 years) were included from three different centers. Neurosurgical tissue samples were available in all patients and revealed a brain somatic variant in SLC35A2 in six patients (non-present in the blood). After 6 months of supplementation, D-galactose was well tolerated with just two patients presenting abdominal discomfort, solved after dose spacing or reduction. There was a 50% reduction or higher of seizure frequency in 3/6 patients, with an improvement at EEG in 2/5 patients. One patient became seizure-free. An improvement of cognitive/behavioral features encompassing impulsivity (mean SNAP-IV - 3.19 [- 0.84; - 5.6]), social communication (mean SCQ - 2.08 [- 0.63; - 4.90]), and executive function (BRIEF-2 inhibit - 5.2 [- 1.23; - 9.2]) was observed. Global responder rate was 9/12 (6/6 in SLC35A2-positive). Our results suggest that supplementation with D-galactose in patients with MOGHE is safe and well tolerated and, although the efficacy data warrant larger studies, it might build a rationale for precision medicine after epilepsy surgery.


Asunto(s)
Epilepsia , Galactosa , Humanos , Medicina de Precisión , Hiperplasia , Proyectos Piloto , Calidad de Vida , Epilepsia/terapia , Convulsiones , Electroencefalografía/métodos
10.
Nat Commun ; 14(1): 2779, 2023 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-37188705

RESUMEN

Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood-brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis.


Asunto(s)
Envejecimiento , Antidepresivos , Harmina , Mitocondrias , Mitofagia , Monoaminooxidasa , Receptores de GABA-A , Harmina/análogos & derivados , Harmina/farmacología , Antidepresivos/farmacología , Mitocondrias/efectos de los fármacos , Mitofagia/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Quinasas de la Proteína-Quinasa Activada por el AMP/metabolismo , Músculo Esquelético/efectos de los fármacos , Hígado/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Resistencia a la Insulina , Intolerancia a la Glucosa/metabolismo , Estado Prediabético/metabolismo , Monoaminooxidasa/metabolismo , Receptores de GABA-A/metabolismo , Longevidad/efectos de los fármacos , Caenorhabditis elegans , Drosophila melanogaster , Fragilidad/prevención & control , Condicionamiento Físico Animal , Modelos Animales , Masculino , Femenino , Animales , Ratones , Hígado Graso/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos
11.
J Neurosci ; 30(3): 905-15, 2010 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-20089899

RESUMEN

Neuroblastoma is a pediatric tumor that is thought to arise from autonomic precursors in the neural crest. Mutations in the PHOX2B gene have been observed in familial and sporadic forms of neuroblastoma and represent the first defined genetic predisposition for neuroblastoma. Here, we address the mechanisms that may underlie this predisposition, comparing the function of wild-type and mutant Phox2b proteins ectopically expressed in proliferating, embryonic sympathetic neurons. Phox2b displays a strong antiproliferative effect, which is lost in all Phox2b neuroblastoma variants analyzed. In contrast, an increase in sympathetic neuron proliferation is elicited by Phox2b variants with mutations in the homeodomain when endogenous Phox2b levels are lowered by siRNA-mediated knockdown to mimic the situation of heterozygous PHOX2B mutations in neuroblastoma. The increased proliferation is blocked by Hand2 knockdown and the antiproliferative Phox2b effects are rescued by Hand2 overexpression, implying Hand2 in Phox2b-mediated proliferation control. A Phox2b variant with a nonsense mutation in the homeodomain elicits, in addition, a decreased expression of characteristic marker genes. Together, these results suggest that PHOX2B mutations predispose to neuroblastoma by increasing proliferation and promoting dedifferentiation of cells in the sympathoadrenergic lineage.


Asunto(s)
Diferenciación Celular/fisiología , Proliferación Celular , Ganglios Simpáticos/citología , Proteínas de Homeodominio/fisiología , Mutación/fisiología , Factores de Transcripción/fisiología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factor Neurotrófico Derivado del Encéfalo/farmacología , Bromodesoxiuridina/metabolismo , Recuento de Células/métodos , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Embrión de Pollo , Embrión de Mamíferos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Histonas/metabolismo , Proteínas de Homeodominio/química , Proteínas de Homeodominio/genética , Inmunoprecipitación , Proteína 2 Inhibidora de la Diferenciación/genética , Proteína 2 Inhibidora de la Diferenciación/metabolismo , Ratones , Ratones Endogámicos C57BL , Neuroblastoma , Neuronas , ARN Interferente Pequeño/farmacología , Factores de Transcripción/química , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Tirosina 3-Monooxigenasa/metabolismo
12.
Biochem Biophys Res Commun ; 412(3): 435-40, 2011 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-21821005

RESUMEN

Inhibitory glycine receptors (GlyRs) are densely packed in the postsynaptic membrane due to a high-affinity interaction of their ß-subunits with the scaffolding protein gephyrin. Here, we used an affinity-based proteomic approach to identify the trafficking proteins Vacuolar Protein Sorting 35 (Vps35) and Neurobeachin (Nbea) as novel GlyR ß-subunit (GlyRß) interacting proteins in rat brain. Recombinant Vps35 and a central fragment of Nbea bound to the large intracellular loop of GlyRß in glutathione-S-transferase pull-downs; in addition, Vps35 displayed binding to gephyrin. Immunocytochemical staining of spinal cord sections revealed Nbea immunoreactivity apposed to and colocalizing with marker proteins of inhibitory synapses. Our data are consistent with roles of Vps35 and Nbea in the retrieval and post-Golgi trafficking of synaptic GlyRs and possibly other neurotransmitter receptors.


Asunto(s)
Encéfalo/metabolismo , Receptores de Glicina/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animales , Proteínas Portadoras/metabolismo , Línea Celular , Aparato de Golgi/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Transporte de Proteínas , Proteómica/métodos , Ratas , Receptores de Glicina/genética , Médula Espinal , Sinapsis/metabolismo , Proteínas de Transporte Vesicular/genética
13.
Front Cell Dev Biol ; 9: 770458, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34957103

RESUMEN

The serotonergic system of mammals innervates virtually all the central nervous system and regulates a broad spectrum of behavioral and physiological functions. In mammals, serotonergic neurons located in the rostral raphe nuclei encompass diverse sub-systems characterized by specific circuitry and functional features. Substantial evidence suggest that functional diversity of serotonergic circuits has a molecular and connectivity basis. However, the landscape of intrinsic developmental mechanisms guiding the formation of serotonergic sub-systems is unclear. Here, we employed developmental disruption of gene expression specific to serotonergic subsets to probe the contribution of the tyrosine kinase receptor ErbB4 to serotonergic circuit formation and function. Through an in vivo loss-of-function approach, we found that ErbB4 expression occurring in a subset of serotonergic neurons, is necessary for axonal arborization of defined long-range projections to the forebrain but is dispensable for the innervation of other targets of the serotonergic system. We also found that Erbb4-deletion does not change the global excitability or the number of neurons with serotonin content in the dorsal raphe nuclei. In addition, ErbB4-deficiency in serotonergic neurons leads to specific behavioral deficits in memory processing that involve aversive or social components. Altogether, our work unveils a developmental mechanism intrinsically acting through ErbB4 in subsets of serotonergic neurons to orchestrate a precise long-range circuit and ultimately involved in the formation of emotional and social memories.

14.
Front Cell Neurosci ; 14: 283, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33132842

RESUMEN

Critical periods of brain development are epochs of heightened plasticity driven by environmental influence necessary for normal brain function. Recent studies are beginning to shed light on the possibility that timely interventions during critical periods hold potential to reorient abnormal developmental trajectories in animal models of neurological and neuropsychiatric disorders. In this review, we re-examine the criteria defining critical periods, highlighting the recently discovered mechanisms of developmental plasticity in health and disease. In addition, we touch upon technological improvements for modeling critical periods in human-derived neural networks in vitro. These scientific advances associated with the use of developmental manipulations in the immature brain of animal models are the basic preclinical systems that will allow the future translatability of timely interventions into clinical applications for neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD) and schizophrenia.

15.
Elife ; 92020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33320083

RESUMEN

The assembly of specific neuronal circuits relies on the expression of complementary molecular programs in presynaptic and postsynaptic neurons. In the cerebral cortex, the tyrosine kinase receptor ErbB4 is critical for the wiring of specific populations of GABAergic interneurons, in which it paradoxically regulates both the formation of inhibitory synapses as well as the development of excitatory synapses received by these cells. Here, we found that Nrg1 and Nrg3, two members of the neuregulin family of trophic factors, regulate the inhibitory outputs and excitatory inputs of interneurons in the mouse cerebral cortex, respectively. The differential role of Nrg1 and Nrg3 in this process is not due to their receptor-binding EGF-like domain, but rather to their distinctive subcellular localization within pyramidal cells. Our study reveals a novel strategy for the assembly of cortical circuits that involves the differential subcellular sorting of family-related synaptic proteins.


Asunto(s)
Corteza Cerebral/metabolismo , Neurregulina-1/metabolismo , Neurregulinas/metabolismo , Células Piramidales/metabolismo , Sinapsis/metabolismo , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neurregulina-1/genética , Neurregulinas/genética , Receptor ErbB-4/genética , Receptor ErbB-4/metabolismo , Transducción de Señal/fisiología
16.
Adv Lab Med ; 1(2): 20200021, 2020 Jun.
Artículo en Inglés, Español | MEDLINE | ID: mdl-37363778

RESUMEN

Objectives: The stability of the analytes most commonly used in routine clinical practice has been the subject of intensive research, with varying and even conflicting results. Such is the case of alanine aminotransferase (ALT). The purpose of this study was to determine the stability of serum ALT according to different variables. Methods: A multicentric study was conducted in eight laboratories using serum samples with known initial catalytic concentrations of ALT within four different ranges, namely: <50 U/L (<0.83 µkat/L), 50-200 U/L (0.83-3.33 µkat/L), 200-400 U/L (3.33-6.67 µkat/L) and >400 U/L (>6.67 µkat/L). Samples were stored for seven days at two different temperatures using four experimental models and four laboratory analytical platforms. The respective stability equations were calculated by linear regression. A multivariate model was used to assess the influence of different variables. Results: Catalytic concentrations of ALT decreased gradually over time. Temperature (-4%/day at room temperature vs. -1%/day under refrigeration) and the analytical platform had a significant impact, with Architect (Abbott) showing the greatest instability. Initial catalytic concentrations of ALT only had a slight impact on stability, whereas the experimental model had no impact at all. Conclusions: The constant decrease in serum ALT is reduced when refrigerated. Scarcely studied variables were found to have a significant impact on ALT stability. This observation, added to a considerable inter-individual variability, makes larger studies necessary for the definition of stability equations.

18.
Biochem Med (Zagreb) ; 30(1): 010704, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31839724

RESUMEN

INTRODUCTION: Diabetes mellitus (DM) is one of the most prevalent diseases worldwide. The objective of this study was to find out under what preanalytical conditions routine and diagnostic glucose tests are performed across Spanish laboratories; and also what criteria are used for DM diagnosis. MATERIALS AND METHODS: An online survey was performed by the Commission on Quality Assurance in the Extra-Analytical Phase of the Spanish Society of Laboratory Medicine (SEQC-ML). Access to the questionnaire was available on the home page of the SEQC-ML website during the period April-July 2018. Data analysis was conducted with the IBM SPSS© Statistics (version 20.0) program. RESULTS: A total of 96 valid surveys were obtained. Most laboratories were in public ownership, serving hospital and primary care patients, with high and medium workloads, and a predominance of mixed routine-urgent glucose testing. Serum tubes were the most used for routine glucose analysis (92%) and DM diagnosis (54%); followed by lithium-heparin plasma tubes (62%), intended primarily for urgent glucose testing; point-of-care testing devices were used by 37%; and plasma tubes with a glycolysis inhibitor, mainly sodium fluoride, by 19%. Laboratories used the cut-off values and criteria recognized worldwide for DM diagnosis in adults and glucose-impaired tolerance, but diverged in terms of fasting plasma glucose and gestational DM criteria. CONCLUSION: Preanalytical processing of routine and DM diagnostic glucose testing in Spain does not allow a significant, non-quantified influence of glycolysis on the results to be ruled out. Possible adverse consequences include a delay in diagnosis and possible under-treatment.


Asunto(s)
Glucemia/análisis , Recolección de Muestras de Sangre/métodos , Recolección de Muestras de Sangre/instrumentación , Diabetes Mellitus/diagnóstico , Humanos , Laboratorios de Hospital/normas , Fase Preanalítica , España , Encuestas y Cuestionarios
19.
Curr Opin Neurobiol ; 48: 174-182, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29329089

RESUMEN

Neuropsychiatric disorders arise from the alteration of normal brain developmental trajectories disrupting the function of specific neuronal circuits. Recent advances in human genetics have greatly accelerated the identification of genes whose variation increases the susceptibility for neurodevelopmental disorders, most notably for autism spectrum disorder (ASD) and schizophrenia. In parallel, experimental studies in animal models-most typically in mice-are beginning to shed light on the role of these genes in the development and function of specific brain circuits. In spite of their limitations, understanding the impact of pathological gene variation in animal models at the level of specific neuronal populations and circuits will likely contribute to orienting human clinical studies in the search for precise disease mechanisms and novel treatments.


Asunto(s)
Encéfalo/patología , Modelos Animales de Enfermedad , Red Nerviosa/fisiopatología , Vías Nerviosas/fisiopatología , Trastornos del Neurodesarrollo/patología , Animales , Encéfalo/fisiopatología , Ratones
20.
Nat Neurosci ; 20(6): 784-792, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28394324

RESUMEN

The function of cortical GABAergic interneurons is largely determined by their integration into specific neural circuits, but the mechanisms controlling the wiring of these cells remain largely unknown. This is particularly true for a major population of basket cells that express the neuropeptide cholecystokinin (CCK). Here we found that the tyrosine kinase receptor ErbB4 was required for the normal integration into cortical circuits of basket cells expressing CCK and vesicular glutamate transporter 3 (VGlut3). The number of inhibitory synapses made by CCK+VGlut3+ basket cells and the inhibitory drive they exerted on pyramidal cells were reduced in conditional mice lacking ErbB4. Developmental disruption of the connectivity of these cells diminished the power of theta oscillations during exploratory behavior, disrupted spatial coding by place cells, and caused selective alterations in spatial learning and memory in adult mice. These results suggest that normal integration of CCK+ basket cells in cortical networks is key to support spatial coding in the hippocampus.


Asunto(s)
Corteza Cerebral/fisiología , Colecistoquinina/fisiología , Neuronas GABAérgicas/fisiología , Aprendizaje Espacial/fisiología , Memoria Espacial/fisiología , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animales , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiología , Corteza Cerebral/metabolismo , Colecistoquinina/genética , Colecistoquinina/metabolismo , Conducta Exploratoria/fisiología , Neuronas GABAérgicas/metabolismo , Interneuronas/metabolismo , Interneuronas/fisiología , Locomoción/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , Inhibición Neural/fisiología , Vías Nerviosas/fisiología , Células de Lugar/fisiología , Inhibición Prepulso/fisiología , Células Piramidales/fisiología , Receptor ErbB-4/biosíntesis , Receptor ErbB-4/genética , Receptor ErbB-4/fisiología , Ritmo Teta/fisiología
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