Glutamate transporter modulation of ambient and synaptic glutamate levels

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. An accurate spatial and temporal glutamate concentration profile during signaling is crucial for reliable neural computation. In these studies, we investigated the roles of glutamate transporters in controlling both ambient glutamate levels and dynamic glutamate concentrations profiles during synaptic transmission. Using the Xenopus oocyte expression system, we demonstrated that glutamate transporters act as an effective sink and are capable of maintaining \u3e200 fold glutamate concentration gradient between the bath and cell surface when expressed at levels corresponding to physiological transporter densities in the CNS. We also characterized the specificity and actions of a new arylasparate glutamate transport inhibitor at the Shaffer collateral-CA1 pyramidal cell synapse in hippocampus, and demonstrated that glial glutamate transporters tightly control synaptically released glutamate and further, through cooperation with voltage-dependent Mg2+ block, they influence the magnitude and frequency-dependence of postsynaptic NMDA receptor signaling

Covariate-assisted ranking and screening for large-scale two-sample inference

Two-sample multiple testing has a wide range of applications. The conventionalpractice first reduces the original observations to a vector of p-values and then chooses a cutoffto adjust for multiplicity. However, this data reduction step could cause significant loss ofinformation and thus lead to suboptimal testing procedures.We introduce a new framework fortwo-sample multiple testing by incorporating a carefully constructed auxiliary variable in inferenceto improve the power. A data-driven multiple-testing procedure is developed by employinga covariate-assisted ranking and screening (CARS) approach that optimally combines the informationfrom both the primary and the auxiliary variables. The proposed CARS procedureis shown to be asymptotically valid and optimal for false discovery rate control. The procedureis implemented in the R package CARS. Numerical results confirm the effectiveness of CARSin false discovery rate control and show that it achieves substantial power gain over existingmethods. CARS is also illustrated through an application to the analysis of a satellite imagingdata set for supernova detection

The impact of gender and age on risk-taking attitudes

1 online resource (ii, 16 p.)Includes abstract.Includes bibliographical references (p. 11-12).This paper investigates the extent of gender difference in attitudes towards risk, and its persistence across age-cohorts. Pooled micro data based on Canadian Surveys of Household Spending, conducted annually from 1996 to 2009, are used to estimate a multivariate regression equation. Also, by creating a panel data and using random effect method, presence of any statistically significant difference across Canadian provinces in insurance spending over this period is investigated. The multivariate regression estimates show that, in accordance with the previous literature, females are more risk averse than males. The gender risk-aversion gap appears to be closing for younger cohorts. The panel estimation reveals a pattern consistent with a positive relationship with mean income and expenditure on home-insurance

Effects of Synaptic Frequency and Glutamate Transport on NMDA Receptor Activity at the Shaffer-CA1 Synapse

Glutamate is the predominant excitatory neurotransmitter in the central nervous system and it plays a central role in many processes including perception, learning, and memory. Glutamate transporters are thought to help maintain synapse specificity in the hippocampus by limiting spillover of glutamate. The NMDA subtype of glutamate receptor (NMDAR) is a key player in neuronal plasticity and serves as a coincidence detector by requiring binding of transmitter in addition to postsynaptic membrane depolarization to relieve Mg2+ block. While inhibition of glutamate transport has been shown to cause increased NMDAR activity in conditions permissive for receptor signaling, such as in the absence of extracellular Mg2+, the roles of transport in physiological conditions are less well understood. In this work we show that in Mg2+-free conditions, increasing release site density prolonged the time course of EPSCs and fEPSPs evoked at low frequency by enhancing NMDAR activity, consistent with published work by several groups. However, in physiological [Mg2+], this effect was not observed. NMDAR fEPSPs were selectively enhanced by repetitive activity in a frequency range that closely matched the decay kinetics of [Mg2+]-blocked NMDAR channels monitored with depolarizing voltage pulses. Glutamate transporter inhibition in physiological [Mg2+] increased NMDAR signaling in the same frequency-dependent manner. The data suggest that at low frequencies, Mg2+ block rather than glutamate transport plays a dominant role in restricting extrasynaptic NMDAR activity, and that a pool of glutamate-bound and Mg2+-blocked NMDARs signal in a phase-shifted manner during repetitive synaptic activity at frequencies governed by channel desensitization and transmitter unbinding. The data also suggest a potential mechanism contributing to theta frequency-dependent associative LTP

Glutamate transporter control of ambient glutamate levels

Accurate knowledge of the ambient extracellular glutamate concentration in brain is required for understanding its potential impacts on tonic and phasic receptor signaling. Estimates of ambient glutamate based on microdialysis measurements are generally in the range of ∼2–10 μM, approximately 100-fold higher than estimates based on electrophysiological measurements of tonic NMDA receptor activity (∼25–90 nM). The latter estimates are closer to the low nanomolar estimated thermodynamic limit of glutamate transporters. The reasons for this discrepancy are not known, but it has been suggested that microdialysis measurements could overestimate ambient extracellular glutamate because of reduced glutamate transporter activity in a region of metabolically impaired neuropil adjacent to the dialysis probe. We explored this issue by measuring diffusion gradients created by varying membrane densities of glutamate transporters expressed in Xenopus oocytes. With free diffusion from a pseudo-infinite 10 μM glutamate source, the surface concentration of glutamate depended on transporter density and was reduced over 2 orders of magnitude by transporters expressed at membrane densities similar to those previously reported in hippocampus. We created a diffusion model to simulate the effect of transport impairment on microdialysis measurements with boundary conditions corresponding to a 100 μm radius probe. A gradient of metabolic disruption in a thin (∼100 μm) region of neuropil adjacent to the probe increased predicted [Glu] in the dialysate over 100-fold. The results provide support for electrophysiological estimates of submicromolar ambient extracellular [Glu] in brain and provide a possible explanation for the higher values reported using microdialysis approaches

Specificity and Actions of an Arylaspartate Inhibitor of Glutamate Transport at the Schaffer Collateral-CA1 Pyramidal Cell Synapse

In this study we characterized the pharmacological selectivity and physiological actions of a new arylaspartate glutamate transporter blocker, L-threo-ß-benzylaspartate (L-TBA). At concentrations up to 100 µM, L-TBA did not act as an AMPA receptor (AMPAR) or NMDA receptor (NMDAR) agonist or antagonist when applied to outside-out patches from mouse hippocampal CA1 pyramidal neurons. L-TBA had no effect on the amplitude of field excitatory postsynaptic potentials (fEPSPs) recorded at the Schaffer collateral-CA1 pyramidal cell synapse. Excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons were unaffected by L-TBA in the presence of physiological extracellular Mg2+ concentrations, but in Mg2+-free solution, EPSCs were significantly prolonged as a consequence of increased NMDAR activity. Although L-TBA exhibited approximately four-fold selectivity for neuronal EAAT3 over glial EAAT1/EAAT2 transporter subtypes expressed in Xenopus oocytes, the L-TBA concentration-dependence of the EPSC charge transfer increase in the absence of Mg2+ was the same in hippocampal slices from EAAT3 +/+ and EAAT3 −/− mice, suggesting that TBA effects were primarily due to block of glial transporters. Consistent with this, L-TBA blocked synaptically evoked transporter currents in CA1 astrocytes with a potency in accord with its block of heterologously expressed glial transporters. Extracellular recording in the presence of physiological Mg2+ revealed that L-TBA prolonged fEPSPs in a frequency-dependent manner by selectively increasing the NMDAR-mediated component of the fEPSP during short bursts of activity. The data indicate that glial glutamate transporters play a dominant role in limiting extrasynaptic transmitter diffusion and binding to NMDARs. Furthermore, NMDAR signaling is primarily limited by voltage-dependent Mg2+ block during low-frequency activity, while the relative contribution of transport increases during short bursts of higher frequency signaling

Organizing memories for generalization in complementary learning systems

Memorization and generalization are complementary cognitive processes that jointly promote adaptive behavior. For example, animals should memorize safe routes to specific water sources and generalize from these memories to discover environmental features that predict new ones. These functions depend on systems consolidation mechanisms that construct neocortical memory traces from hippocampal precursors, but why systems consolidation only applies to a subset of hippocampal memories is unclear. Here we introduce a new neural network formalization of systems consolidation that reveals an overlooked tension—unregulated neocortical memory transfer can cause overfitting and harm generalization in an unpredictable world. We resolve this tension by postulating that memories only consolidate when it aids generalization. This framework accounts for partial hippocampal–cortical memory transfer and provides a normative principle for reconceptualizing numerous observations in the field. Generalization-optimized systems consolidation thus provides new insight into how adaptive behavior benefits from complementary learning systems specialized for memorization and generalization

I run as fast as a rabbit, can you? A Multilingual Simile Dialogue Dataset

A simile is a figure of speech that compares two different things (called the tenor and the vehicle) via shared properties. The tenor and the vehicle are usually connected with comparator words such as "like" or "as". The simile phenomena are unique and complex in a real-life dialogue scene where the tenor and the vehicle can be verbal phrases or sentences, mentioned by different speakers, exist in different sentences, or occur in reversed order. However, the current simile research usually focuses on similes in a triplet tuple (tenor, property, vehicle) or a single sentence where the tenor and vehicle are usually entities or noun phrases, which could not reflect complex simile phenomena in real scenarios. In this paper, we propose a novel and high-quality multilingual simile dialogue (MSD) dataset to facilitate the study of complex simile phenomena. The MSD is the largest manually annotated simile data ($\sim$20K) and it contains both English and Chinese data. Meanwhile, the MSD data can also be used on dialogue tasks to test the ability of dialogue systems when using similes. We design 3 simile tasks (recognition, interpretation, and generation) and 2 dialogue tasks (retrieval and generation) with MSD. For each task, we provide experimental results from strong pre-trained or state-of-the-art models. The experiments demonstrate the challenge of MSD and we have released the data/code on GitHub.Comment: 13 Pages, 1 Figure, 12 Tables, ACL 2023 finding