GluN3A and excitatory glycine receptors in the adult hippocampus.

The GluN3A subunit of N-methyl-D-aspartate receptors (NMDARs) plays an established role in synapse development, but its contribution to neural circuits in the adult brain is less clear. Recent work has demonstrated that in select cell populations, GluN3A assembles with GluN1 to form GluN1/GluN3A receptors that are insensitive to glutamate and instead serve as functional excitatory glycine receptors (eGlyRs). Our understanding of these eGlyRs, and how they contribute to intrinsic excitability and synaptic communication within relevant networks of the developing and the mature brain, is only beginning to be uncovered. Here, using male and female mice, we demonstrate that GluN3A subunits are enriched in the adult ventral hippocampus (VH), where they localize to synaptic and extrasynaptic sites and can assemble as functional eGlyRs on CA1 pyramidal cells. GluN3A expression was barely detectable in the adult dorsal hippocampus (DH). We also observed a high GluN2B content in the adult VH, characterized by slow NMDAR current decay kinetics and a high sensitivity to the GluN2B-containing NMDAR antagonist ifenprodil. Interestingly, the GluN2B enrichment in the adult VH was dependent on GluN3A as GluN3A deletion accelerated NMDAR decay and reduced ifenprodil sensitivity in the VH, suggesting that GluN3A expression can regulate the balance of conventional NMDAR subunit composition at synaptic sites. Lastly, we found that GluN3A knockout also enhanced both NMDAR-dependent calcium influx and NMDAR-dependent long-term potentiation in the VH. Together, these data reveal a novel role for GluN3A and eGlyRs in the control of ventral hippocampal circuits in the mature brain.Significance statement Glutamate is the brain's most abundant excitatory neurotransmitter. One of its most common receptors is the NMDA receptor (NMDAR), composed of a variety of subunits. Here, we show that an atypical NMDAR subunit, GluN3A, is enriched in the ventral hippocampus, where it forms a receptor that is no longer sensitive to glutamate. Instead, it acts as an excitatory receptor for glycine, normally an inhibitory transmitter. We show that GluN3A plays essential roles in the adult ventral hippocampus, modulating transmitter release probability, conventional NMDAR subunit composition, calcium entry, and synaptic plasticity. These findings are important as they shed light on the role of GluN3A and these newly discovered excitatory glycine receptors in the mature brain.

Asymmetric dysregulation of glutamate dynamics across the synaptic cleft in a mouse model of Alzheimer's disease.

Most research on glutamate spillover focuses on the deleterious consequences of postsynaptic glutamate receptor overactivation. However, two decades ago, it was noted that the glial coverage of hippocampal synapses is asymmetric: astrocytic coverage of postsynaptic sites exceeds coverage of presynaptic sites by a factor of four. The fundamental relevance of this glial asymmetry remains poorly understood. Here, we used the glutamate biosensor iGluSnFR, and restricted its expression to either CA3 or CA1 neurons to visualize glutamate dynamics at pre- and postsynaptic microenvironments, respectively. We demonstrate that inhibition of the primarily astrocytic glutamate transporter-1 (GLT-1) slows glutamate clearance to a greater extent at presynaptic compared to postsynaptic membranes. GLT-1 expression was reduced early in a mouse model of AD, resulting in slower glutamate clearance rates at presynaptic but not postsynaptic membranes that opposed presynaptic short-term plasticity. Overall, our data demonstrate that the presynapse is particularly vulnerable to GLT-1 dysfunction and may have implications for presynaptic impairments in a variety of brain diseases.

Actitudes hacia la sexualidad en adolescentes de bachillerato de la ciudad de Querétaro, México / Attitudes toward sexuality among high school adolescents in Queretaro city, Mexico

INTRODUCCIÓN. La sexualidad forma parte de cada etapa de la vida del ser humano, no obstante, en la adolescencia existe una pérdida de orientación, presión social por parte de sus iguales e información no precisa, lo que conduce a un inicio temprano de la vida sexual y consecuencias no deseadas. OBJETIVO. Determinar la actitud en adolescentes de bachillerato, hacia la sexualidad. METODOLOGÍA. Estudio transversal, descriptivo, realizado en el Colegio de Bachilleres del Estado de Querétaro, Plantel 1. El instrumento se denomina "Actitudes hacia el sexo", diseñado y validado en población queretana en 2017. RESULTADOS. Se aplicaron 264 instrumentos en jóvenes con edades de 15 a 16 años. Con respecto a las actitudes hacia el sexo, 32,6% no saben por qué tendrían sexo. Indican que les acarrearía mala reputación o pérdida de respeto hacia su persona si tuvieran relaciones sexuales, el 19,7% y 18,9%, respectivamente. Podrían sentirse culpables después de hacer el acto sexual el 22,3%. Tienen curiosidad de vivir la experiencia el 23,5%. Han iniciado con la práctica de relaciones sexuales el 38,6% aproximadamente a los 15 años, la mayoría. 6,1% ha tenido relaciones sin uso de un método de barrera y bajo el efecto del alcohol. CONCLUSIONES. La información obtenida refleja la necesidad de trabajar con los estudiantes en valores, inteligencia emocional, violencia, perspectivas de género, que favorezcan una visión clara de la sexualidad y una apropiada toma de decisiones.

INTRODUCTION. Sexuality is part of every stage of human life, however in adolescence the loss of orientation, social pressure from peers, and inaccurate information often leads to an early onset of sexual life and unwanted consequences. OBJECTIVE. To determine the attitude of high school adolescents towards sexuality. METHODOLOGY. Cross-sectional, descriptive study, conducted at High School Colegio de Bachilleres del Estado de Querétaro, Plantel 1. An instrument called "Attitudes towards sex" was designed and validated in the Queretano population in 2017. RESULTS. 264 instruments were administered to adolescents aged 15 to 16 years. With respect to attitudes towards sex, 32.6% did not know why they tend to have sex. Respondents were concerned that sex could result in a bad reputation (19.7%) or loss of their own self-respect (18.9%). Students could also feel guilty after sex (22.3%). 23.5% had curiosity about have sex. 28.6% of the teenagers surveyed started their sexual life at an average of 15 years; most of them have had sex without the use of a condom and under the influence of alcohol. CONCLUSIONS. The information obtained shows the necessity to work with the values, emotional intelligence, violence, and gender perspectives of adolescent students to help them develop a better perspective about sexuality and make appropriate decisions.

Huntingtin and the Synapse.

Huntington disease (HD) is a monogenic disease that results in a combination of motor, psychiatric and cognitive symptoms. HD is caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which results in the production of a pathogenic mutant HTT protein (mHTT). Although there is no cure at present for HD, a number of RNA-targeting therapies have recently entered clinical trials which aim to lower mHTT production through the use of antisense oligonucleotides (ASOs) and RNAi. However, many of these treatment strategies are non-selective in that they cannot differentiate between non-pathogenic wild type HTT (wtHTT) and the mHTT variant. As HD patients are already born with decreased levels of wtHTT, these genetic therapies may result in critically low levels of wtHTT. The consequence of wtHTT reduction in the adult brain is currently under debate, and here we argue that wtHTT loss is not well-tolerated at the synaptic level. Synaptic dysfunction is an extremely sensitive measure of subsequent cell death, and is known to precede neurodegeneration in numerous brain diseases including HD. The present review focuses on the prominent role of wtHTT at the synapse and considers the consequences of wtHTT loss on both pre- and postsynaptic function. We discuss how wtHTT is implicated in virtually all major facets of synaptic neurotransmission including anterograde and retrograde transport of proteins to/from terminal buttons and dendrites, neurotransmitter release, endocytic vesicle recycling, and postsynaptic receptor localization and recycling. We conclude that wtHTT presence is essential for proper synaptic function.

The Effect of GLT-1 Upregulation on Extracellular Glutamate Dynamics.

Pharmacological upregulation of glutamate transporter-1 (GLT-1), commonly achieved using the beta-lactam antibiotic ceftriaxone, represents a promising therapeutic strategy to accelerate glutamate uptake and prevent excitotoxic damage in neurological conditions. While excitotoxicity is indeed implicated in numerous brain diseases, it is typically restricted to select vulnerable brain regions, particularly in early disease stages. In healthy brain tissue, the speed of glutamate uptake is not constant and rather varies in both an activity- and region-dependent manner. Despite the widespread use of ceftriaxone in disease models, very little is known about how such treatments impact functional measures of glutamate uptake in healthy tissue, and whether GLT-1 upregulation can mask the naturally occurring activity-dependent and regional heterogeneities in uptake. Here, we used two different compounds, ceftriaxone and LDN/OSU-0212320 (LDN), to upregulate GLT-1 in healthy wild-type mice. We then used real-time imaging of the glutamate biosensor iGluSnFR to investigate functional consequences of GLT-1 upregulation on activity- and regional-dependent variations in glutamate uptake capacity. We found that while both ceftriaxone and LDN increased GLT-1 expression in multiple brain regions, they did not prevent activity-dependent slowing of glutamate clearance nor did they speed basal clearance rates, even in areas characterized by slow uptake (e.g., striatum). Unexpectedly, ceftriaxone but not LDN decreased glutamate release in the cortex, suggesting that ceftriaxone may alter release properties independent of its effects on GLT-1 expression. In sum, our data demonstrate the complexities of glutamate uptake by showing that GLT-1 expression does not necessarily translate to accelerated uptake. Furthermore, these data suggest that the mechanisms underlying activity- and regional-dependent differences in glutamate dynamics are independent of GLT-1 expression levels.

Super-resolution imaging reveals extrastriatal synaptic dysfunction in presymptomatic Huntington disease mice.

Synaptic structure and function are compromised prior to cell death and symptom onset in a variety of neurodegenerative diseases. In Huntington disease (HD), a CAG repeat expansion in the gene encoding the huntingtin protein results in a presymptomatic stage that typically spans multiple decades and is followed by striking degeneration of striatal tissue and the progression of debilitating motor symptoms. Many lines of evidence demonstrate that the HD presymptomatic window is associated with injurious effects to striatal synapses, many of which appear to be prerequisites to subsequent cell death. While the striatum is the most vulnerable region in the HD brain, it is widely recognized that HD is a brain-wide disease, affecting numerous extrastriatal regions that contribute to debilitating non-motor symptoms including cognitive dysfunction. Currently, we have a poor understanding of the synaptic integrity, or lack thereof, in extrastriatal regions in the presymptomatic HD brain. If early therapeutic intervention seeks to maintain healthy synaptic function, it is important to understand early HD-associated synaptopathy at a brain-wide, rather than striatal-exclusive, level. Here, we focused on the hippocampus as this structure is generally thought to be affected only in manifest HD despite the subtle cognitive deficits known to emerge in prodromal HD. We used super-resolution microscopy and multi-electrode array electrophysiology as sensitive measures of excitatory synapse structure and function, respectively, in the hippocampus of presymptomatic heterozygous HD mice (Q175FDN model). We found clear evidence for enhanced AMPA receptor subunit clustering and hyperexcitability well before the onset of a detectable HD-like behavioral phenotype. In addition, activity-dependent re-organization of synaptic protein nanostructure, and functional measures of synaptic plasticity were impaired in presymptomatic HD mice. These data demonstrate that synaptic abnormalities in the presymptomatic HD brain are not exclusive to the striatum, and highlight the need to better understand the region-dependent complexities of early synaptopathy in the HD brain.

Iodized salt sales in the United States.

Iodized salt has been an important source of dietary iodine, a trace element important for regulating human growth, development, and metabolic functions. This analysis identified iodized table salt sales as a percentage of retail salt sales using Nielsen ScanTrack. We identified 1117 salt products, including 701 salt blends and 416 other salt products, 57 of which were iodized. When weighted by sales volume in ounces or per item, 53% contained iodized salt. These findings may provide a baseline for future monitoring of sales of iodized salt.