Distribution of Extracellular Glutamate in the Neuropil of Hippocampus

Reported values of extracellular glutamate concentrations in the resting state depend on the method of measurement and vary ∼1000-fold. As glutamate levels in the micromolar range can cause receptor desensitization and excitotoxicity, and thus affect neuronal excitability, an accurate determination of ambient glutamate is important. Part of the variability of previous measurements may have resulted from the sampling of glutamate in different extracellular compartments, e.g., synaptic versus extrasynaptic volumes. A steep concentration gradient of glutamate between these two compartments could be maintained, for example, by high densities of glutamate transporters arrayed at the edges of synapses. We have used two photon laser scanning microscopy and electrophysiology to investigate whether extracellular glutamate is compartmentalized in acute hippocampal slices. Pharmacological blockade of NMDARs had no effect on Ca2+ transients generated in dendritic shafts or spines of CA1 pyramidal neurons by depolarization, suggesting that ambient glutamate is too low to activate a significant number of NMDARs. Furthermore, blockade of transporters did not flood the synapse with glutamate, indicating that synaptic NMDARs are not protected from high concentrations of extrasynaptic glutamate. We suggest that, in the CA1 region of hippocampus, glutamate transporters do not create a privileged space within the synapse but rather keep ambient glutamate at very low levels throughout the neuropil

Diet-Derived Fatty Acids, Brain Inflammation, and Mental Health

Western societies experienced drastic changes in eating habits during the past century. The modern nutritional profile, typically rich in saturated fats and refined sugars, is recognized as a major contributing factor, along with reduced physical activity, to the current epidemics of metabolic disorders, notably obesity and diabetes. Alongside these conditions, recent years have witnessed a gradual and significant increase in prevalence of brain diseases, particularly mood disorders. While substantial clinical/epidemiological evidence supports a correlation between metabolic and neuropsychiatric disorders, the mechanisms of pathogenesis in the latter are often multifactorial and causal links have been hard to establish. Neuroinflammation stands out as a hallmark feature of brain disorders that may be linked to peripheral metabolic dyshomeostasis caused by an unhealthy diet. Dietary fatty acids are of particular interest, as they may play a dual role, both as a component of high-calorie obesogenic diets and as signaling molecules involved in inflammatory responses. Here, we review current literature connecting diet-related nutritional imbalance and neuropsychiatric disorders, focusing on the role of dietary fatty acids as signaling molecules directly relevant to inflammatory processes and to neuronal function

Modifier Adaptation as a Feedback Control Scheme

As a real-time optimization technique, modifier adaptation (MA) has gained much significance in recent years. This is mainly due to the fact that MA can deal explicitly with structural plant-model mismatch and unknown disturbances. MA is an iterative technique that is ideally suited to real-life applications. Its two main features are the way measurements are used to correct the model and the role played by the model in actually computing the next inputs. This paper analyzes these two features and shows that, although MA computes the next inputs via numerical optimization, it can be viewed as a feedback control scheme, that is, optimization implements tracking of the plant Karush-Kuhn-Tucker (KKT) conditions. As a result, the role of the model is downplayed to the point that model accuracy is not an important issue. The key issues are gradient estimation and model adequacy, the latter requiring that the model possesses the correct curvature of the cost function at the plant optimum. The main role of optimization is to identify the proper set of controlled variables (the active constraints and reduced gradients) as these might change with the operating point and disturbances. Thanks to this reduced requirement on model accuracy, MA is ideally suited to drive real-life processes to optimality. This is illustrated through two experimental systems with very different optimization features, namely, a commercial fuel-cell system and an experimental kite setup for harnessing wind energy.Fil: Marchetti, Alejandro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas. Universidad Nacional de Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas; ArgentinaFil: de Avila Ferreira, T.. Ecole Polytechnique Federale de Lausanne; FranciaFil: Costello, Sergio Gustavo. Ecole Polytechnique Federale de Lausanne; FranciaFil: Bonvin, Dominique. Ecole Polytechnique Federale de Lausanne; Franci

Elevated Glutamate and Glutamine Levels in the Cerebrospinal Fluid of Patients With Probable Alzheimer's Disease and Depression

Recent evidence suggests that Alzheimer's disease (AD) and depression share common mechanisms of pathogenesis. In particular, deregulation of glutamate-mediated excitatory signaling may play a role in brain dysfunction in both AD and depression. We have investigated levels of glutamate and its precursor glutamine in the cerebrospinal fluid (CSF) of patients with a diagnosis of probable AD or major depression compared to healthy controls and patients with hydrocephalus. Patients with probable AD or major depression showed significantly increased CSF levels of glutamate and glutamine compared to healthy controls or hydrocephalus patients. Furthermore, CSF glutamate and glutamine levels were inversely correlated to the amyloid tau index, a biomarker for AD. Results suggest that glutamate and glutamine should be further explored as potential CSF biomarkers for AD and depression

Human apolipoprotein A-I natural variants: molecular mechanisms underlying amyloidogenic propensity

Human apolipoprotein A-I (apoA-I)-derived amyloidosis can present with either wild-type (Wt) protein deposits in atherosclerotic plaques or as a hereditary form in which apoA-I variants deposit causing multiple organ failure. More than 15 single amino acid replacement amyloidogenic apoA-I variants have been described, but the molecular mechanisms involved in amyloid-associated pathology remain largely unknown. Here, we have investigated by fluorescence and biochemical approaches the stabilities and propensities to aggregate of two disease-associated apoA-I variants, apoA-IGly26Arg, associated with polyneuropathy and kidney dysfunction, and apoA-ILys107-0, implicated in amyloidosis in severe atherosclerosis. Results showed that both variants share common structural properties including decreased stability compared to Wt apoA-I and a more flexible structure that gives rise to formation of partially folded states. Interestingly, however, distinct features appear to determine their pathogenic mechanisms. ApoA-ILys107-0 has an increased propensity to aggregate at physiological pH and in a pro-inflammatory microenvironment than Wt apoA-I, whereas apoA-IGly26Arg elicited macrophage activation, thus stimulating local chronic inflammation. Our results strongly suggest that some natural mutations in apoA-I variants elicit protein tendency to aggregate, but in addition the specific interaction of different variants with macrophages may contribute to cellular stress and toxicity in hereditary amyloidosis

Dynamic Microtubules Promote Synaptic NMDA Receptor-Dependent Spine Enlargement

Most excitatory synaptic terminals in the brain impinge on dendritic spines. We and others have recently shown that dynamic microtubules (MTs) enter spines from the dendritic shaft. However, a direct role for MTs in long-lasting spine plasticity has yet to be demonstrated and it remains unclear whether MT-spine invasions are directly influenced by synaptic activity. Lasting changes in spine morphology and synaptic strength can be triggered by activation of synaptic NMDA receptors (NMDARs) and are associated with learning and memory processes. To determine whether MTs are involved in NMDAR-dependent spine plasticity, we imaged MT dynamics and spine morphology in live mouse hippocampal pyramidal neurons before and after acute activation of synaptic NMDARs. Synaptic NMDAR activation promoted MT-spine invasions and lasting increases in spine size, with invaded spines exhibiting significantly faster and more growth than non-invaded spines. Even individual MT invasions triggered rapid increases in spine size that persisted longer following NMDAR activation. Inhibition of either NMDARs or dynamic MTs blocked NMDAR-dependent spine growth. Together these results demonstrate for the first time that MT-spine invasions are positively regulated by signaling through synaptic NMDARs, and contribute to long-lasting structural changes in targeted spines

Theoretical and experimental study on electron interactions with chlorobenzene: Shape resonances and differential cross sections

In this work, we report theoretical and experimental cross sections for elastic scattering of electrons by chlorobenzene (ClB). The theoretical integral and differential cross sections (DCSs) were obtained with the Schwinger multichannel method implemented with pseudopotentials (SMCPP) and the independent atom method with screening corrected additivity rule (IAM-SCAR). The calculations with the SMCPP method were done in the static-exchange (SE) approximation, for energies above 12 eV, and in the static-exchange plus polarization approximation, for energies up to 12 eV. The calculations with the IAM-SCAR method covered energies up to 500 eV. The experimental differential cross sections were obtained in the high resolution electron energy loss spectrometer VG-SEELS 400, in Lisbon, for electron energies from 8.0 eV to 50 eV and angular range from 7 degrees to 110 degrees. From the present theoretical integral cross section (ICS) we discuss the low-energy shape-resonances present in chlorobenzene and compare our computed resonance spectra with available electron transmission spectroscopy data present in the literature. Since there is no other work in the literature reporting differential cross sections for this molecule, we compare our theoretical and experimental DCSs with experimental data available for the parent molecule benzene. Published by AIP Publishing

Blood Levels of Glutamate and Glutamine in Recent Onset and Chronic Schizophrenia

Converging evidence indicates that dysfunctions in glutamatergic neurotransmission and in the glutamate-glutamine cycle play a role in the pathophysiology of schizophrenia. Here, we investigated glutamate and glutamine levels in the blood of patients with recent onset schizophrenia or chronic schizophrenia compared to healthy controls. Compared with healthy controls, patients with recent onset schizophrenia showed increased glutamine/glutamate ratio, while patients with chronic schizophrenia showed decreased glutamine/glutamate ratio. Results indicate that circulating glutamate and glutamine levels exhibit a dual behavior in schizophrenia, with an increase of glutamine/glutamate ratio at the onset of schizophrenia followed by a decrease with progression of the disorder. Further studies are warranted to elucidate the mechanisms and consequences of changes in circulating glutamate and glutamine in schizophrenia

MeerKLASS: MeerKAT Large Area Synoptic Survey

We discuss the ground-breaking science that will be possible with a wide area survey, using the MeerKAT telescope, known as MeerKLASS (MeerKAT Large Area Synoptic Survey). The current specifications of MeerKAT make it a great fit for science applications that require large survey speeds but not necessarily high angular resolutions. In particular, for cosmology, a large survey over $\sim 4,000 \, {\rm deg}^2$ for $\sim 4,000$ hours will potentially provide the first ever measurements of the baryon acoustic oscillations using the 21cm intensity mapping technique, with enough accuracy to impose constraints on the nature of dark energy. The combination with multi-wavelength data will give unique additional information, such as exquisite constraints on primordial non-Gaussianity using the multi-tracer technique, as well as a better handle on foregrounds and systematics. Such a wide survey with MeerKAT is also a great match for HI galaxy studies, providing unrivalled statistics in the pre-SKA era for galaxies resolved in the HI emission line beyond local structures at z > 0.01. It will also produce a large continuum galaxy sample down to a depth of about 5\,$\mu$Jy in L-band, which is quite unique over such large areas and will allow studies of the large-scale structure of the Universe out to high redshifts, complementing the galaxy HI survey to form a transformational multi-wavelength approach to study galaxy dynamics and evolution. Finally, the same survey will supply unique information for a range of other science applications, including a large statistical investigation of galaxy clusters as well as produce a rotation measure map across a huge swathe of the sky. The MeerKLASS survey will be a crucial step on the road to using SKA1-MID for cosmological applications and other commensal surveys, as described in the top priority SKA key science projects (abridged).Comment: Larger version of the paper submitted to the Proceedings of Science, "MeerKAT Science: On the Pathway to the SKA", Stellenbosch, 25-27 May 201