Astroglial Connexins Inactivation Increases Relapse of Depressive-like Phenotype after Antidepressant Withdrawal.

Studies suggest that astrocytic connexins (Cx) have an important role in the regulation of high brain functions through their ability to establish fine-tuned communication with neurons within the tripartite synapse. In light of these properties, growing evidence suggests a role of Cx in psychiatric disorders such as major depression but also in the therapeutic activity of antidepressant drugs. However, the real impact of Cx on treatment response and the underlying neurobiological mechanisms remain yet to be clarified. On this ground, the present study was designed to evaluate the functional activity of Cx in a mouse model of depression based on chronic corticosterone exposure and to determine to which extent their pharmacological inactivation influences the antidepressant-like activity of venlafaxine (VENLA). On the one hand, our results indicate that depressed mice have impaired Cx-based gap-junction and hemichannel activities. On the other hand, while VENLA exerts robust antidepressant-like activity in depressed mice; this effect is abolished by the pharmacological inhibition of Cx with carbenoxolone (CBX). Interestingly, the combination of VENLA and CBX is also associated with a higher rate of relapse after treatment withdrawal. To our knowledge, this study is one of the first to develop a model of relapse, and our results reveal that Cx-mediated dynamic neuroglial interactions play a critical role in the efficacy of monoaminergic antidepressant drugs, thus providing new targets for the treatment of depression.

Astrocytes close the mouse critical period for visual plasticity.

Brain postnatal development is characterized by critical periods of experience-dependent remodeling of neuronal circuits. Failure to end these periods results in neurodevelopmental disorders. The cellular processes defining critical-period timing remain unclear. Here, we show that in the mouse visual cortex, astrocytes control critical-period closure. We uncover the underlying pathway, which involves astrocytic regulation of the extracellular matrix, allowing interneuron maturation. Unconventional astrocyte connexin signaling hinders expression of extracellular matrix-degrading enzyme matrix metalloproteinase 9 (MMP9) through RhoA-guanosine triphosphatase activation. Thus, astrocytes not only influence the activity of single synapses but also are key elements in the experience-dependent wiring of brain circuits.

Exposición y riesgo ocupacional de covid-19 en estudiantes, docentes y profesionales de la salud / Exposure and occupational risk of covid-19 in students, teachers and health professionals

La exposición de los profesionales de la salud al nuevo coronavirus (SARS-CoV-2) así como el riesgo de adquirir su enfermedad asociada (COVID-19) es más alta en comparación a otros grupos poblacionales. La correcta implementación de medidas de bioseguridad puede reducir su riesgo de infección. El objetivod e este estudio fue evaluar la disponibilidad de insumos y Equipos Personales de Protección (EPP), las exigencias y riesgos ocupacionales y su relación con el COVID-19. Pacientes y métodos Estudio observacional descriptivo de corte transversal que incluyó a 603 participantes entre estudiantes, docentes de una universidad pública y profesionales de la salud. Las mediciones principales fueron: exposición ocupacional e incidencia de COVID-19. Resultados El 73,5% de encuestados fueron mujeres, el 92,6% adultos jóvenes y el 23,55% (IC95% 20,3-27,1) refirió diagnóstico de COVID-19 (15% confirmado, 8% sospechoso). Laborar en la provincia de Pichincha y no disponer de jabón se asoció con diagnóstico de COVID-19 (OR ajustado= 2.85 y 2.68 respectivamente). El contacto con casos confirmados y sospechosos fueron las variables que presentaron asociaciones más fuertes con la enfermedad (OR ajustado= 9.28 y 3.07 respectivamente). Conclusiones La alta incidencia de COVID-19 en los encuestados se asoció con deficiencias en la disponibilidad de EPP. La protección de profesionales de salud debe ser una prioridad para las autoridades de salud y trabajo, quienes además deben brindar los EPP e insumos necesarios. Recomendamos el tamizaje periódico de este grupo ocupacional para evaluar el impacto de las medidas de protección y analizar la implementación de correcciones necesarias.

Health professional's exposure to the new coronavirus (SARS-CoV-2) as well as their risk of acquiring COVID-19 "its associated disease", has been higher compared to other population groups. Nevertheless, the correct implementation of biosecurity measures could reduce their infection risk. The objective of this study was to evaluate the availability of personal protective equipment "PPE", occupational risks and its relationship with COVID-19 in health professionals. Patients and methods 603 subjects among students, teachers, and health professionals were included in a crosssectional descriptive observational study. Occupational exposure and incidence of COVID-19 were the main measurements. Results Most of the subjects were women (73.5%) and young adults (92.6%) and 23.55% (95% CI 20.3- 27.1) referred a diagnosis of COVID-19 (15% confirmed, 8% suspected). People who worked in Pichincha's province and those who did not have soap presented a higher risk of COVID-19 infection (adjusted OR= 2.85 and 2.68 respectively). Contact with confirmed and suspicious cases were the variables that were associated with the highest risk of infection (adjusted OR= 9.28 and 3.07 respectively). Conclusions The high incidence of COVID-19 in the subjects was associated with PPE deficiencies. Health professional's protection must be a priority for health and labor authorities, who must also provide the PPE and necessary supplies. A periodic screening in this occupational group to assess the impact of protective measures and analyze the implementation of necessary corrections.is recommended.

TSPAN5 Enriched Microdomains Provide a Platform for Dendritic Spine Maturation through Neuroligin-1 Clustering.

Tetraspanins are a class of evolutionarily conserved transmembrane proteins with 33 members identified in mammals that have the ability to organize specific membrane domains, named tetraspanin-enriched microdomains (TEMs). Despite the relative abundance of different tetraspanins in the CNS, few studies have explored their role at synapses. Here, we investigate the function of TSPAN5, a member of the tetraspanin superfamily for which mRNA transcripts are found at high levels in the mouse brain. We demonstrate that TSPAN5 is localized in dendritic spines of pyramidal excitatory neurons and that TSPAN5 knockdown induces a dramatic decrease in spine number because of defects in the spine maturation process. Moreover, we show that TSPAN5 interacts with the postsynaptic adhesion molecule neuroligin-1, promoting its correct surface clustering. We propose that membrane compartmentalization by tetraspanins represents an additional mechanism for regulating excitatory synapses.

Condiciones sociodemográfcas post terremoto relacionadas a los Conocimientos, Actitudes y Prácticas de Zika, Nuevo Pedernales - Ecuador / Post-earthquake socio-demographic conditions related to Zika Knowledge, Attitudes and Practices, Nuevo Pedernales ­ Ecuador

En el Ecuador, el brote de Zika coincidió con el terremoto en la ciudad de Pedernales, Provincia de Manabí. No se han realizado estudios de Conocimientos, Actitudes y Practicas (CAP) de Zika en condiciones post terremoto. Objetivo: Evaluar las diferencias de CAP de Zika según las características sociodemográfcas y género de las personas entre 15 y 49 años. Pacientes y Métodos: Estudio de corte transversal. Se analizaron las características sociodemográfcas, los antecedentes de Enfermedad de Transmisión Vectorial (ETV) y CAP de Zika entre 122 jefes de familia y 148 personas entre 15 y 49 años, moradores de Nuevo Pedernales, Manabí - Ecuador. Resultados: La mitad de encuestados tuvieron conocimientos adecuados, un tercio presentó actitud protectora y el promedio de prácticas preventivas frente al Zika fue bajo (5 de 9). Las personas que no dormían en la cocina y tenían servicio eléctrico presentaron puntajes mayores de conocimientos con tamaño de efecto débil (DM= 1,46; Etacuadrado= 0,037 y DM= 3,9; Eta- cuadrado= 0,036 respectivamente). Las personas diagnosticadas previamente de ETV tuvieron mayor número de prácticas preventivas empleadas con tamaño de efecto moderado (DM=1,16; Eta-cuadrado= 0,062). Los mismos presentaron mayor puntuación de CAP total con tamaño de efecto moderado (DM= 2,80; Eta cuadrado= 0,058). Conclusión: Los encuestados tienen niveles bajos de CAP y presentan alto riesgo de transmisión de Zika y otras ETV. Las entidades gubernamentales deben implementar programas intensivos de educación comunitaria, mejorar las condiciones precarias de vivienda y el acceso a servicios básicos.

In Ecuador, the Zika's outbreak coincided with Pedernales earthquake. There have not been studies of Knowledge, Attitudes and Practices (KAP) of Zika in post-earthquake conditions. Objective: To evaluate Zika´s KAP according to gender and sociodemographic characteristics of people aged 15 to 49. Patients and Methods: Cross-sectional study. Sociodemographic characteristics, history of Vector-Borne Disease (VBD) and Zika's KAP were analyzed between 122 heads of households and 148 people aged 15 to 49 years dwellers in Nuevo Pedernales, Manabí - Ecuador. Results: Half of the respondents had adequate knowledge, a third presented a protective attitude and the average of preventive practices against Zika was low (5 of 9). In knowledge, people who didn't sleep in the kitchen had higher scores with a weak effect size (DM= 1,46; Eta-square = 0,037) and people who had electricity also had higher scores with weak effect size (DM= 3,9; Eta-square = 0,036). People diagnosed with a Vector-Borne Disease (VBD) after the earthquake had an average of a greater number of preventive practices employed with moderate effect size (DM= 1,16; Eta-square=0,062). This same group had a higher KAP score with moderate effect size (DM= 2,80; Eta-square = 0,058). Conclusions: Respondents have low levels of KAP and high risk of Zika and other VBD's transmission. Government entities must implement intensive community education programs and improve precarious housing conditions and basic services access.

Versatile control of synaptic circuits by astrocytes: where, when and how?

Close structural and functional interactions of astrocytes with synapses play an important role in brain function. The repertoire of ways in which astrocytes can regulate synaptic transmission is complex so that they can both promote and dampen synaptic efficacy. Such contrasting effects raise questions regarding the determinants of these divergent astroglial functions. Recent findings provide insights into where, when and how astroglial regulation of synapses takes place by revealing major molecular and functional intrinsic heterogeneity as well as switches in astrocytes occurring during development or specific patterns of neuronal activity. Astrocytes may therefore be seen as boosters or gatekeepers of synaptic circuits depending on their intrinsic and transformative properties throughout life.

Epilepsy and intellectual disability linked protein Shrm4 interaction with GABABRs shapes inhibitory neurotransmission.

Shrm4, a protein expressed only in polarized tissues, is encoded by the KIAA1202 gene, whose mutations have been linked to epilepsy and intellectual disability. However, a physiological role for Shrm4 in the brain is yet to be established. Here, we report that Shrm4 is localized to synapses where it regulates dendritic spine morphology and interacts with the C terminus of GABAB receptors (GABABRs) to control their cell surface expression and intracellular trafficking via a dynein-dependent mechanism. Knockdown of Shrm4 in rat severely impairs GABABR activity causing increased anxiety-like behaviour and susceptibility to seizures. Moreover, Shrm4 influences hippocampal excitability by modulating tonic inhibition in dentate gyrus granule cells, in a process involving crosstalk between GABABRs and extrasynaptic δ-subunit-containing GABAARs. Our data highlights a role for Shrm4 in synaptogenesis and in maintaining GABABR-mediated inhibition, perturbation of which may be responsible for the involvement of Shrm4 in cognitive disorders and epilepsy.

eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures.

Alterations in the balance of inhibitory and excitatory synaptic transmission have been implicated in the pathogenesis of neurological disorders such as epilepsy. Eukaryotic elongation factor 2 kinase (eEF2K) is a highly regulated, ubiquitous kinase involved in the control of protein translation. Here, we show that eEF2K activity negatively regulates GABAergic synaptic transmission. Indeed, loss of eEF2K increases GABAergic synaptic transmission by upregulating the presynaptic protein Synapsin 2b and α5-containing GABAA receptors and thus interferes with the excitation/inhibition balance. This cellular phenotype is accompanied by an increased resistance to epilepsy and an impairment of only a specific hippocampal-dependent fear conditioning. From a clinical perspective, our results identify eEF2K as a potential novel target for antiepileptic drugs, since pharmacological and genetic inhibition of eEF2K can revert the epileptic phenotype in a mouse model of human epilepsy.

Myosin IXa Binds AMPAR and Regulates Synaptic Structure, LTP, and Cognitive Function.

Myosin IXa (Myo9a) is a motor protein that is highly expressed in the brain. However, the role of Myo9a in neurons remains unknown. Here, we investigated Myo9a function in hippocampal synapses. In rat hippocampal neurons, Myo9a localizes to the postsynaptic density (PSD) and binds the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) GluA2 subunit. Myo9a(+/-) mice displayed a thicker PSD and increased levels of PSD95 and surface AMPAR expression. Furthermore, synaptic transmission, long-term potentiation (LTP) and cognitive functions were impaired in Myo9a(+/-) mice. Together, these results support a key role for Myo9a in controlling the molecular structure and function of hippocampal synapses.

Activity-Dependent Plasticity of Astroglial Potassium and Glutamate Clearance.

Recent evidence has shown that astrocytes play essential roles in synaptic transmission and plasticity. Nevertheless, how neuronal activity alters astroglial functional properties and whether such properties also display specific forms of plasticity still remain elusive. Here, we review research findings supporting this aspect of astrocytes, focusing on their roles in the clearance of extracellular potassium and glutamate, two neuroactive substances promptly released during excitatory synaptic transmission. Their subsequent removal, which is primarily carried out by glial potassium channels and glutamate transporters, is essential for proper functioning of the brain. Similar to neurons, different forms of short- and long-term plasticity in astroglial uptake have been reported. In addition, we also present novel findings showing robust potentiation of astrocytic inward currents in response to repetitive stimulations at mild frequencies, as low as 0.75 Hz, in acute hippocampal slices. Interestingly, neurotransmission was hardly affected at this frequency range, suggesting that astrocytes may be more sensitive to low frequency stimulation and may exhibit stronger plasticity than neurons to prevent hyperexcitability. Taken together, these important findings strongly indicate that astrocytes display both short- and long-term plasticity in their clearance of excess neuroactive substances from the extracellular space, thereby regulating neuronal activity and brain homeostasis.

Astroglial calcium signaling displays short-term plasticity and adjusts synaptic efficacy.

Astrocytes are dynamic signaling brain elements able to sense neuronal inputs and to respond by complex calcium signals, which are thought to represent their excitability. Such signaling has been proposed to modulate, or not, neuronal activities ranging from basal synaptic transmission to epileptiform discharges. However, whether calcium signaling in astrocytes exhibits activity-dependent changes and acutely modulates short-term synaptic plasticity is currently unclear. We here show, using dual recordings of astroglial calcium signals and synaptic transmission, that calcium signaling in astrocytes displays, concomitantly to excitatory synapses, short-term plasticity in response to prolonged repetitive and tetanic stimulations of Schaffer collaterals. We also found that acute inhibition of calcium signaling in astrocytes by intracellular calcium chelation rapidly potentiates excitatory synaptic transmission and short-term plasticity of Shaffer collateral CA1 synapses, i.e., paired-pulse facilitation and responses to tetanic and prolonged repetitive stimulation. These data reveal that calcium signaling of astrocytes is plastic and down-regulates basal transmission and short-term plasticity of hippocampal CA1 glutamatergic synapses.

The neurobiology of X-linked intellectual disability.

X-linked intellectual disability (XLID) affects 1% to 3% of the population. XLID subsumes several heterogeneous conditions, all of which are marked by cognitive impairment and reduced adaptive skills. XLID arises from mutations on the X chromosome; to date, 102 XLID genes have been identified. The proteins encoded by XLID genes are involved in higher brain functions, such as cognition, learning and memory, and their molecular role is the subject of intense investigation. Here, we review recent findings concerning a representative group of XLID proteins: the fragile X mental retardation protein; methyl-CpG-binding protein 2 and cyclin-dependent kinase-like 5 proteins, which are involved in Rett syndrome; the intracellular signaling molecules of the Rho guanosine triphosphatases family; and the class of cell adhesion molecules. We discuss how XLID gene mutations affect the structure and function of synapses.

AMPAR trafficking in synapse maturation and plasticity.

Glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate most fast excitatory synaptic transmission in the central nervous system. The content and composition of AMPARs in postsynaptic membranes (which determine synaptic strength) are dependent on the regulated trafficking of AMPAR subunits in and out of the membranes. AMPAR trafficking is a key mechanism that drives nascent synapse development, and is the main determinant of both Hebbian and homeostatic plasticity in mature synapses. Hebbian plasticity seems to be the biological substrate of at least some forms of learning and memory; while homeostatic plasticity (also known as synaptic scaling) keeps neuronal circuits stable by maintaining changes within a physiological range. In this review, we examine recent findings that provide further understanding of the role of AMPAR trafficking in synapse maturation, Hebbian plasticity, and homeostatic plasticity.

Activation of subthalamic alpha 2 noradrenergic receptors induces motor deficits as a consequence of neuronal burst firing.

The subthalamic nucleus (STN) plays a key role in the pathophysiology of Parkinson's disease. This was demonstrated by the fact that STN neurons express more bursts in animal models of the disease and by the ability of STN inactivation to alleviate motor deficits. However, the origin of the bursts and the causal link between STN bursts and motor deficits remain unknown. The present study aimed to investigate the role of noradrenergic receptor modulation on the firing activity of STN neurons and the impact of this modulation on locomotor activity in sham and 6-hydroxydopamine-lesioned rats. Using selective agonists and antagonists of α1- and α2-adrenergic receptors (AR), we show that local infusion of clonidine, an α2-AR agonist, induced a switch from tonic to bursty pattern without changing the firing rate. This change in the pattern was prevented by the local infusion of idazoxan, an α2-AR antagonist. Furthermore, clonidine injection into the STN reduced locomotor activity in sham and 6-hydroxydopamine-lesioned rats. In contrast, local injection of phenylephrine, an α1-AR agonist, increased the firing rate of STN neurons without changing the firing pattern. In parallel, phenylephrine did not change locomotor activity. This is the first evidence showing the implication of α1-ARs in the modulation of firing rate and α2-ARs in the modulation of the firing pattern of STN neurons. Furthermore, our data provide also evidence that activation of the STN α2-ARs plays a key role in the genesis of subthalamic burst activity, which may be at the origin of motor deficits.

The X-linked intellectual disability protein TSPAN7 regulates excitatory synapse development and AMPAR trafficking.

Mutations in TSPAN7--a member of the tetraspanin protein superfamily--are implicated in some forms of X-linked intellectual disability. Here we show that TSPAN7 overexpression promotes the formation of filopodia and dendritic spines in cultured hippocampal neurons from embryonic rats, whereas TSPAN7 silencing reduces head size and stability of spines and AMPA receptor currents. Via its C terminus, TSPAN7 interacts with the PDZ domain of protein interacting with C kinase 1 (PICK1), to regulate PICK1 and GluR2/3 association and AMPA receptor trafficking. These findings indicate that, in hippocampal neurons, TSPAN7 regulates AMPA receptor trafficking by limiting PICK1 accessibility to AMPA receptors and suggest an additional mechanism for the functional maturation of glutamatergic synapses, whose impairment is implicated in intellectual disability.

Contenido de flúor en bebidas de consumo frecuente por niños en edad de riesgo de fluorosis dental. Medellín, 2006 / Fluoride content in beverages of frequent intake by children at risk age of dental fluorosis. Medellín, 2006

Introducción: igual a lo sucedido en otros lugares del mundo, la prevalencia de la fluorosis dental se ha incrementado en Medellín concomitantemente con la reducción de la caries dental. Estos cambios han sido atribuidos al amplio uso, tanto sistémico como tópico, del flúor. El objetivo de este estudio fue determinar el contenido de flúor en las bebidas consumidas por niños y niñas en edad de riesgo para la fluorosis dental. Métodos: varios tipos de bebidas (agua embotellada, bebidas lácteas, jugos naturales, gaseosas, refrescos, energizantes y té) de 40 marcas comerciales distintas, compradas en supermercados y tiendas de barrio, fueron analizadas. El contenido de flúor de todas las muestras de bebidas fue determinado por duplicado mediante el método de microdifusión, usando un electrodo selectivo para el ion flúor. Resultados: las concentraciones de flúor oscilaron entre 0,010 a 4,285 mg/L. La mayoría de las bebidas presentaron concentraciones de flúor por debajo de 0,058 mg/L. La más alta concentración de flúor fue encontrada en las bebidas a base de té (3,45 ± 1,49 mg/L; rango 1,54-4,28 mg/L). Las etiquetas de los fabricantes no informaban acerca de la concentración de flúor en las bebidas analizadas. Conclusiones: la mayoría de las bebidas no alcanzaban concentraciones de flúor que pudieran ser consideradas de riesgo para la fluorosis, sin embargo algunas de las bebidas analizadas podrían hacer una contribución importante a la ingestión diaria de flúor. Su consumo por los niños y niñas en edad de riesgo de sufrir fluorosis debe ser evitado. El contenido de flúor de estos productos debería ser informado por el fabricante en las etiquetas de presentación.