Disruption of striatal glutamatergic transmission induced by mutant huntingtin involves remodelling of both postsynaptic density and NMDA receptor signalling

We study the striatal susceptibility to NMDA receptor (NMDAR)-mediated injury of two Huntington’s disease (HD) transgenic mice:R6/1 and R6/1:BDNF+/−. We found that R6/1:BDNF+/− mice – whichexpress reduced levels of BDNF – were more resistant than R6/1 miceto intrastriatal injection of quinolinate. This increased resistance isrelated to a differential reduction in expression of NMDAR scaffoldingproteins, MAGUKs (PSD-95, PSD-93, SAP-102 and SAP-97) but notto altered levels or synaptic location of NMDAR. A robust reorganizationof postsynaptic density (PSD) was detected in HD transgenicmice, shown by a switch of PSD-93 by PSD-95 in PSD. Furthermore,NMDAR signaling pathways were affected by different BDNF levels inHD mice; we found a reduction of synaptic αCaMKII (but not ofnNOS) in R6/1:BDNF+/− compared to R6/1 mice. The specific regulationof MAGUKs and αCaMKII in striatal neurons may reflect aprotective mechanism against expression of mutant huntingtin exon-1

Objetos virtuales de aprendizaje para ciencias de la salud

[EN] From the beginning, the "Bologna Declaration" sought to achieve full university homologation given the heterogeneity of European educational systems. In this environment, where professional practices are combined with continuous assessment and personalized tutoring, the use of the Internet-ICT binomial enhances teaching methods and speeds up knowledge acquisition times. Universities must integrate them to train competent professionals. Some technologies that make use of ICT are Augmented Reality (AR) and Virtual Reality (VR). These allow the creation of educational content capable of supporting the teaching-learning process, such as Virtual Learning Objects (OVA). Objective: To develop multiple OVAs for the training of students and professionals in nursing and health sciences. Methodology: Study where various OVAs are generated divided into three blocks [Theoretical Foundations (FT), Basic Clinical Practice (PCB), Advanced Clinical Practice (PCA)]. Each block contains a series of teaching units that will be dealt with using VR / AR. The materials are generated by a multidisciplinary group of professionals working collaboratively. Results: materials have been generated in poster format, virtual tours and mental health interventions. Conclusion: The interaction between professionals generates educational materials in OVA format that can be used by health sciences students and promote their learning.[ES] Desde un primer momento, la “Declaración de Bolonia” buscó lograr una total homologación universitaria ante la heterogeneidad de los sistemas educativos europeos. En este espacio, donde las prácticas profesionales se unen con la evaluación continua y la tutoría personalizada, la utilización del binomio Internet-TIC potencia los métodos de enseñanza y agiliza los tiempos de captación de conocimientos. Las universidades deben integrarlas para formar profesionales competentes. Algunas tecnologías que hacen uso de las TIC son la Realidad Aumentada (RA) y Realidad Virtual (RV). Estas permiten crear contenidos educativos capaces de apoyar el proceso de enseñanza-aprendizaje, como son los Objetos Virtuales de Aprendizaje (OVA). Objetivo: Elaborar múltiples OVA para la formación de estudiantes y profesionales de enfermería y ciencias de la salud. Metodología: Estudio donde se generan diversas OVA divididas en tres bloques [Fundamentos Teóricos (FT), Práctica Clínica Básica (PCB), Práctica Clínica Avanzada (PCA)]. Cada bloque contiene una serie de unidades docentes que se tratarán haciendo uso de la RV/RA. Los materiales son generados por un grupo multidisciplinar de profesionales trabajando colaborativamente. Resultados: se han generado materiales en formato póster, tours virtuales e intervenciones de salud mental. Conclusión: La interacción entre profesionales genera materiales educativos en formato OVA que pueden ser utilizados por los alumnos de ciencias de salud y favorecer su aprendizaje.De Castro Peraza, M.; Delgado Rodriguez, N.; Castro Molina, F.; Lorenzo Rocha, N.; Torres Jorge, J.; De Vega De Castro, A.; Alonso Quintana, M.... (2021). Objetos virtuales de aprendizaje para ciencias de la salud. En IN-RED 2021: VII Congreso de Innovación Edicativa y Docencia en Red. Editorial Universitat Politècnica de València. 983-995. https://doi.org/10.4995/INRED2021.2021.13745OCS98399

Transgenic mice overexpressing the full-length neurotrophin receptor TrkC exhibit increased catecholaminergic neuron density in specific brain areas and increased anxiety-like behavior and panic reaction

Accumulating evidence has suggested that neurotrophins participate in the pathophysiology of mood disorders. We have developed transgenic mice overexpressing the full-length neurotrophin-3 receptor TrkC (TgNTRK3) in the central nervous system. TgNTRK3 mice show increased anxiety-like behavior and enhancement of panic reaction in the mouse defense test battery, along with an increase in the number and density of catecholaminergic (tyrosine hydroxylase positive) neurons in locus coeruleus and substantia nigra. Furthermore, treatment of TgNTRK3 mice with diazepam significantly attenuated the anxiety-like behaviors in the plus maze. These results provide evidence for the involvement of TrkC in the development of noradrenergic neurons in the central nervous system with consequences on anxiety-like behavior and panic reaction. Thus, changes in TrkC expression levels could contribute to the phenotypic expression of panic disorder through a trophic effect on noradrenergic neurons in the locus coeruleus. Our results demonstrate that the elevated NT3-TrkC tone via overexpression of TrkC in the brain may constitute a molecular mechanism for the expression of anxiety and anxiety

Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models

Huntington's disease is caused by an expanded polyglutamine repeat in the huntingtin protein (HTT), but the pathophysiological sequence of events that trigger synaptic failure and neuronal loss are not fully understood. Alterations in N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs) have been implicated. Yet, it remains unclear how the HTT mutation affects NMDAR function, and direct evidence for a causative role is missing. Here we show that mutant HTT redirects an intracellular store of juvenile NMDARs containing GluN3A subunits to the surface of striatal neurons by sequestering and disrupting the subcellular localization of the endocytic adaptor PACSIN1, which is specific for GluN3A. Overexpressing GluN3A in wild-type mouse striatum mimicked the synapse loss observed in Huntington's disease mouse models, whereas genetic deletion of GluN3A prevented synapse degeneration, ameliorated motor and cognitive decline and reduced striatal atrophy and neuronal loss in the YAC128 Huntington's disease mouse model. Furthermore, GluN3A deletion corrected the abnormally enhanced NMDAR currents, which have been linked to cell death in Huntington's disease and other neurodegenerative conditions. Our findings reveal an early pathogenic role of GluN3A dysregulation in Huntington's disease and suggest that therapies targeting GluN3A or pathogenic HTT-PACSIN1 interactions might prevent or delay disease progression

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Estudio de los mecanismos implicados en la neurodegeneración estriatal en modelos murinos de la enfermedad de Huntington

[spa] La memoria titulada "Estudio de los mecanismos implicados en la neurodegeneración estriatal en modelos murinos de la enfermedad de Huntington" ha perseguido determinar la implicación de las neurotrofinas endógenas BDNF y la NT-3 en la susceptibilidad de las neuronas estriatales en modelos transgénicos y excitotóxicos de la enfermedad de Huntington, estudiar la implicación de los agregados intraneuronales y de la excitotoxicidad mediada por los receptores NMDA en modelos transgénicos de la enfermedad de huntington y analizar el potencial de dos aproximaciones terapéuticas para la enfermedad de Huntington basadas en la administración de BDNF intra-estriatal o en el silenciamiento del gen causante de la patología. En dicha memoria se han empleado modelos murinos de la enfermedad de Huntington, el modelo excitotóxico y diversos modelos transgénicos con alteraciones específicas de los niveles de BDNF o la NT-3, ratones condicionales de la huntingtina mutada, así como también cultivos primarios y de precursores neuronales estriatales. Los resultados se han presentado como 3 artículos científicos originales publicados en revistas indexadas ("The Journal of Neuroscience" y "Neuroscience") y un artículo original en fase de preparación. Además, se ha realizado una discusión conjunta de los resultados presentados en los diferentes artículos científicos cumpliendo completamente con lo objetivos planteados. En conjunto, los resultados aportan datos relevantes que ayudan a entender la fisiopatología de la enfermedad de Huntington y la fisiología de las neuronas estriatales. En esta tesis se ha determinado que la disminución de los niveles de neurotrofinas afecta diferencialmente la susceptibilidad de las neuronas estriatales en modelos murinos y excitotóxicos de la enfermedad de Huntington. Así, el BDNF es el factor que modula el inicio y la severidad de la alteraciones motoras asociados a la degeneración selectiva de las neuronas estriatales de proyección en el modelo transgénico R6/1. Por su parte es la NT-3 el factor neurortófco que modula la susceptibilidad excitotóxica de las neuronas estriatales al regular la expresión de los receptores de glutamato tipo NMDA. Además, se ha demostrado que la toxicidad de los agregados intraneuronales presentes en los modelos transgénicos de la enfermedad de Huntington podría depender de su ubicación y el grado de empaquetamiento de la huntingtina dentro del agregado, puesto que dos modelos con el mismo número de agregados estriatales difieren significativamente en el grado de neuropatología estriatal. Además, se logró la reversión total de la patología en un modelo transgénico condicional a pesar de la presencia de agregados de tipo amiloideo, sugiriendo que este tipo de agregados no constituyen la especie más tóxica de la huntingtina mutada. Por último, se ha demostrado que los tratamientos basados en la administración del BDNF o en el silenciamiento del gen de la huntingtina mutada son capaces de revertir ciertas alteraciones neuropatológicas y funcionales de las neuronas estriatales en modelos transgénicos de la enfermedad de Huntington, apoyando la hipótesis de que estas herramientas constituyen alternativas terapéuticas efectivos para la enfermedad de Huntington

Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease

The mechanism that controls the selective vulnerability of striatal neurons in Huntington's disease is unclear. Brain-derived neurotrophic factor (BDNF) protects striatal neurons and is regulated by Huntingtin through the interaction with the neuron-restrictive silencer factor. Here, we demonstrate that the downregulation of BDNF by mutant Huntingtin depends on the length and levels of expression of the CAG repeats in cell cultures. To analyze the functional effects of these changes in BDNF in Huntington's disease, we disrupted the expression of bdnf in a transgenic mouse model by cross-mating bdnf(+/ -) mice with R6/1 mice. Thus, we compared transgenic mice for mutant Huntingtin with different levels of BDNF. Using this double mutant mouse line, we show that the deficit of endogenous BDNF modulates the pathology of Huntington's disease. The decreased levels of this neurotrophin advance the onset of motor dysfunctions and produce more severe uncoordinated movements. This behavioral pathology correlates with the loss of striatal dopamine and cAMP-regulated phosphoprotein-32-positive projection neurons. In particular, the insufficient levels of BDNF cause specific degeneration of the enkephalinergic striatal projection neurons, which are the most affected cells in Huntington's disease. This neuronal dysfunction can specifically be restored by administration of exogenous BDNF. Therefore, the decrease in BDNF levels plays a key role in the specific pathology observed in Huntington's disease by inducing dysfunction of striatal enkephalinergic neurons that produce severe motor dysfunctions. Hence, administration of exogenous BDNF may delay or stop illness progression.This study was supported by Ministerio de Ciencia y Tecnología Grants SAF2002-00314 (J.A.), SAF2002-00311 (J.M.C.), and SAF1999-0123 (G.M.); Redes Temáticas de Investigación Coorporativa (G03/167, G03/210; Ministerio de Sanidad y Consumo); Fundació La Caixa; and Fundación Ramón Areces. J.R.P. is a fellow of the Ministerio de Educación, Cultura y Deporte, J.F.T.-P. is a fellow of the Fundación Gran Mariscal de Ayacucho, M.B. is a fellow of the Universitat de Barcelona, and R.M.-I. is a fellow of the Ministerio de Ciencia y TecnologíaPeer Reviewe

The neuroprotective transcription factor ATF5 is decreased and sequestered into polyglutamine inclusions in Huntington’s disease

Activating transcription factor-5 (ATF5) is a stress-response transcription factor induced upon different cell stressors like fasting, amino-acid limitation, cadmium or arsenite. ATF5 is also induced, and promotes transcription of anti-apoptotic target genes like MCL1, during the unfolded protein response (UPR) triggered by endoplasmic reticulum stress. In the brain, high ATF5 levels are found in gliomas and also in neural progenitor cells, which need to decrease their ATF5 levels for differentiation into mature neurons or glia. This initially led to believe that ATF5 is not expressed in adult neurons. More recently, we reported basal neuronal ATF5 expression in adult mouse brain and its neuroprotective induction during UPR in a mouse model of status epilepticus. Here we aimed to explore whether ATF5 is also expressed by neurons in human brain both in basal conditions and in Huntington’s disease (HD), where UPR has been described to be partially impaired due to defective ATF6 processing. Apart from confirming that ATF5 is present in human adult neurons, here we report accumulation of ATF5 within the characteristic polyglutamine-containing neuronal nuclear inclusions in brains of HD patients and mice. This correlates with decreased levels of soluble ATF5 and of its antiapoptotic target MCL1. We then confirmed the deleterious effect of ATF5 deficiency in a Caenorhabditis elegans model of polyglutamine-induced toxicity. Finally, ATF5 overexpression attenuated polyglutamine-induced apoptosis in a cell model of HD. These results reflect that decreased ATF5 in HD—probably secondary to sequestration into inclusions—renders neurons more vulnerable to mutant huntingtin-induced apoptosis and that ATF5-increasing interventions might have therapeutic potential for HD.CiberNed-ISCIII collaborative Grants PI2013/09-2 and PI2015-2/06-3 and by grants from Spanish Ministry of Economy and Competitiveness (MINECO): SAF2009-08233 and SAF2015-65371-R to JJL, by Fundación BBVA and by Fundación Ramón Arece

Age-dependent decline of motor neocortex but not hippocampal performance in heterozygous BDNF mice correlates with a decrease of cortical PSD-95 but an increase of hippocampal TrkB levels

Brain-derived neurotrophic factor (BDNF) is a key player in learning and memory processes. However, little is known about brain area-specific functions of this neurotrophin. Here we investigated whether BDNF could differently affect motor neocortical and hippocampal-related cognitive and plastic morphologic changes in young (12-week-old) and middle-aged (30-week-old) BDNF heterozygous (BDNF +/-) and wild type (wt) mice. We found that at 30weeks of age, BDNF +/- mice showed impaired performance in accelerating rotarod and grasping tests while preserved spatial learning in a T-maze and recognition memory in an object recognition task compared with wt mice suggesting a specific neocortical dysfunction. Accordingly, a significant reduction of synaptic markers (PSD-95 and GluR1) and corresponding puncta was observed in motor neocortex but not in hippocampus of BDNF +/- mice. Interestingly, 30-week-old BDNF +/- mice displayed increased TrkB levels in the hippocampus but not in the motor neocortex, which suggests specific hippocampal compensatory mechanisms as a consequence of BDNF decrease. In conclusion, our data indicates that BDNF could differentially regulate the neuronal micro-structures and cognition in a region-specific and in an age-dependent manner. © 2012 Elsevier Inc.Ministerio de Ciencia e Innovación (SAF2011-29507, SAF2009-08233, SAF2009-07774, PLE2009-0089, SAF2009-07077; Instituto de Salud Carlos III; CIBERNED; RETICS; Fundación Ramón ArecesPeer Reviewe

Protective neuronal induction of ATF5 in endoplasmic reticulum stress induced by status epilepticus

Activating transcription factor 5 (ATF5) is a basic-leucine-zipper transcription factor of the ATF/CREB family. The Atf5 gene generates two transcripts, Atf5α and Atf5β, of which Atf5α is known to be selectively translated upon endoplasmic reticulum stress response in non-neuronal cells. ATF5 is highly expressed in the developing brain where it modulates proliferation of neural progenitor cells. These cells show a high level of ATF5 that has to decrease to allow them to differentiate into mature neurons or glial cells. This has led to the extended notion that differentiated neural cells do not express ATF5 unless they undergo tumourigenic transformation. However, no systematic analysis of the distribution of ATF5 in adult brain or of its potential role in neuronal endoplasmic reticulum stress response has been reported. By immunostaining here we confirm highest ATF5 levels in neuroprogenitor cells of the embryonic and adult subventricular zone but also found ATF5 in a large variety of neurons in adult mouse brain. By combining Atf5 in situ hybridization and immunohistochemistry for the neuronal marker NeuN we further confirmed Atf5 messenger RNA in adult mouse neurons. Quantitative reverse transcriptase polymerase chain reaction demonstrated that Atf5α is the most abundant transcript in adult mouse encephalon and injection of the endoplasmic reticulum stress inducer tunicamycin into adult mouse brain increased neuronal ATF5 levels. Accordingly, ATF5 levels increased in hippocampal neurons of a mouse model of status epilepticus triggered by intra-amygdala injection of kainic acid, which leads to abnormal hippocampal neuronal activity and endoplasmic reticulum stress. Interestingly, ATF5 upregulation occurred mainly in hippocampal neuronal fields that do not undergo apoptosis in this status epilepticus model such as CA1 and dentate gyrus, thus suggesting a neuroprotective role. This was confirmed in a primary neuronal culture model in which ATF5 overexpression resulted in decreased endoplasmic reticulum stress-induced apoptosis and the opposite result was achieved by Atf5 RNA interference. Furthermore, in vivo administration of the eIF2α phosphatase inhibitor salubrinal resulted in increased ATF5 hippocampal levels and attenuated status epilepticus-induced neuronal death in the vulnerable CA3 subfield. In good agreement with the neuroprotective effect of increased ATF5, we found that apoptosis-resistant epileptogenic foci from patients with temporal lobe epilepsy also showed increased levels of ATF5. Thus, our results demonstrate that adult neurons express ATF5 and that they increase its levels upon endoplasmic reticulum stress as a pro-survival mechanism, thus opening a new field for neuroprotective strategies focused on ATF5 modulation. © 2013 The Author (2013).Peer Reviewe