The long-loop recycling (LLR) of synaptic components as a question of economics.

The pre- and post-synaptic compartments contain a variety of molecules that are known to recycle between the plasma membrane and intracellular organelles. The recycling steps have been amply described in functional terms, with, for example, synaptic vesicle recycling being essential for neurotransmitter release, and postsynaptic receptor recycling being a fundamental feature of synaptic plasticity. However, synaptic protein recycling may also serve a more prosaic role, simply ensuring the repeated use of specific components, thereby minimizing the energy expenditure on the synthesis of synaptic proteins. This type of process has been recently described for components of the extracellular matrix, which undergo long-loop recycling (LLR), to and from the cell body. Here we suggest that the energy-saving recycling of synaptic components may be more widespread than is generally acknowledged, potentially playing a role in both synaptic vesicle protein usage and postsynaptic receptor metabolism.

Assessment of dynamic phase amplitude coupling using matching pursuit.

BACKGROUND: Neuronal transmission and communication are enabled by the interactions across multiple oscillatory frequencies. Phase amplitude coupling (PAC) quantifies these interactions during cognitive brain functions. PAC is defined as the modulation of the amplitude of the high frequency rhythm by the phase of the low frequency rhythm. Existing PAC measures are limited to quantifying the average coupling within a time window of interest. However, as PAC is dynamic, it is necessary to quantify time-varying PAC. Existing time-varying PAC approaches are based on using a sliding window approach. These approaches do not adapt to the signal dynamics, and thus the arbitrary selection of the window length substantially hampers PAC estimation. NEW METHOD: To address the limitations of sliding window PAC estimation approaches, in this paper, we introduce a dynamic PAC measure that relies on matching pursuit (MP). This approach decomposes the signal into time and frequency localized atoms that best describe the signal. Dynamic PAC is quantified by computing the coupling between these time and frequency localized atoms. As such, the proposed approach is data-driven and tracks the change of PAC with time. We evaluate the proposed method on both synthesized and real electroencephalogram (EEG) data. RESULTS: The results from synthesized data show that the proposed method detects the coupled frequencies and the time variation of the coupling correctly with high time and frequency resolution. The analysis of EEG data revealed theta-gamma and alpha-gamma PAC during response and post-response time intervals. COMPARISON WITH EXISTING METHOD(S): Compared to the existing sliding window based approach, the proposed MP based dynamic PAC measure is more effective at capturing PAC within a short time window and is more robust to noise. This is because this method quantifies the low frequency phase and high frequency amplitude components from the time and frequency localized MP atoms and, as such, can capture the signal dynamics. CONCLUSIONS: We posit that the proposed MP based data-driven approach offers a more robust and possibly more sensitive method to effectively quantify and track dynamic PAC.

Recording from an Identified Neuron Efficiently Reveals Hazard for Brain Function in Risk Assessment.

Modern societies use a continuously growing number of chemicals. Because these are released into the environment and are taken up by humans, rigorous (but practicable) risk assessment must precede the approval of new substances for commerce. A number of tests is applicable, but it has been very difficult to efficiently assay the effect of chemicals on communication and information processing in vivo in the adult vertebrate brain. Here, we suggest a straightforward way to rapidly and accurately detect effects of chemical exposure on action potential generation, synaptic transmission, central information processing, and even processing in sensory systems in vivo by recording from a single neuron. The approach is possible in an identified neuron in the hindbrain of fish that integrates various sources of information and whose properties are ideal for rapid analysis of the various effects chemicals can have on the nervous system. The analysis uses fish but, as we discuss here, key neuronal functions are conserved and differences can only be due to differences in metabolism or passage into the brain, factors that can easily be determined. Speed and efficiency of the method, therefore, make it suitable to provide information in risk assessment, as we illustrate here with the effects of bisphenols on adult brain function.

The general anesthetic etomidate and fenamate mefenamic acid oppositely affect GABAAR and GlyR: a structural explanation.

GABA and glycine act as inhibitory neurotransmitters in the CNS. Inhibitory neurotransmission is mediated via activation of ionotropic GABAA and glycine receptors. We used a modeling approach to explain the opposite effects of the general anesthetic etomidate (ETM) and fenamate mefenamic acid (MFA) on GABA- and glycine-activated currents recorded in isolated cerebellar Purkinje cells and hippocampal pyramidal neurons, respectively. These drugs potentiated GABAARs but blocked GlyRs. We built a homology model of α1ß GlyR based on the cryo-EM structure of open α1 GlyR, used the α1ß3γ2 GABAAR structure from the PDB, and applied Monte-Carlo energy minimization to optimize models of receptors and ligand-receptor complexes. In silico docking suggests that ETM/MFA bind at the transmembrane ß( +)/α( -) intersubunit interface in GABAAR. Our models predict that the bulky side chain of the highly conserved Arg19' residue at the plus interface side wedges the interface and maintains the conducting receptor state. We hypothesized that MFA/ETM binding at the ß( +)/α( -) interface leads to prolongation of receptor life-time in the open state. Having analyzed different GABAAR and GlyR structures available in the PDB, we found that mutual arrangement of the Arg19' and Gln-26' side chains at the plus and minus interface sides, respectively, plays an important role when the receptor switches from the open to closed state. We show that this process is accompanied by narrowing of the intersubunit interfaces, leading to extrusion of the Arg19' side chain from the interface. Our models allow us to explain the lack of GlyR potentiation in our electrophysiological experiments.

In vivo assessment of mechanisms underlying the neurovascular basis of postictal amnesia.

Long-lasting confusion and memory difficulties during the postictal state remain a major unmet problem in epilepsy that lacks pathophysiological explanation and treatment. We previously identified that long-lasting periods of severe postictal hypoperfusion/hypoxia, not seizures per se, are associated with memory impairment after temporal lobe seizures. While this observation suggests a key pathophysiological role for insufficient energy delivery, it is unclear how the networks that underlie episodic memory respond to vascular constraints that ultimately give rise to amnesia. Here, we focused on cellular/network level analyses in the CA1 of hippocampus in vivo to determine if neural activity, network oscillations, synaptic transmission, and/or synaptic plasticity are impaired following kindled seizures. Importantly, the induction of severe postictal hypoperfusion/hypoxia was prevented in animals treated by a COX-2 inhibitor, which experimentally separated seizures from their vascular consequences. We observed complete activation of CA1 pyramidal neurons during brief seizures, followed by a short period of reduced activity and flattening of the local field potential that resolved within minutes. During the postictal state, constituting tens of minutes to hours, we observed no changes in neural activity, network oscillations, and synaptic transmission. However, long-term potentiation of the temporoammonic pathway to CA1 was impaired in the postictal period, but only when severe local hypoxia occurred. Lastly, we tested the ability of rats to perform object-context discrimination, which has been proposed to require temporoammonic input to differentiate between sensory experience and the stored representation of the expected object-context pairing. Deficits in this task following seizures were reversed by COX-2 inhibition, which prevented severe postictal hypoxia. These results support a key role for hypoperfusion/hypoxia in postictal memory impairments and identify that many aspects of hippocampal network function are resilient during severe hypoxia except for long-term synaptic plasticity.

Assessment of Long-term Depression Induction in Adult Cerebellar Slices.

Synaptic plasticity provides a mechanism for learning and memory. For cerebellar motor learning, long-term depression (LTD) of synaptic transmissions from parallel fibers (PF) to Purkinje cells (PC) is considered the basis for motor learning, and deficiencies of both LTD and motor learning are observed in various gene-manipulated animals. Common motor learning sets, such as adaptation of the optokinetic reflex (OKR), the vestibular-ocular reflex (VOR), and rotarod test were used for evaluation of motor learning ability. However, results obtained from the GluA2-carboxy terminus modified knock-in mice demonstrated normal adaptation of the VOR and the OKR, despite lacking PF-LTD. In that report, induction of LTD was only attempted using one type of stimulation protocol at room temperature. Thus, conditions to induce cerebellar LTD were explored in the same knock-in mutants using various protocols at near physiological temperature. Finally, we found stimulation protocols, by which LTD could be induced in these gene-manipulated mice. In this study, a set of protocols are proposed to evaluate LTD-induction, which will more accurately allow examination of the causal relationship between LTD and motor learning. In conclusion, experimental conditions are crucial when evaluating LTD in gene-manipulated mice.

Electrophysiology and Behavioral Assessment of the New Molecule SMe1EC2M3 as a Representative of the Future Class of Triple Reuptake Inhibitors.

SMe1EC2M3 is a pyridoindole derivative related to the neuroleptic drug carbidine. Based on the structural similarities of SMe1EC2M3 and known serotonin (5-HT), norepinephrine, and dopamine reuptake inhibitors, we hypothesized that this compound may also have triple reuptake inhibition efficacy and an antidepressant-like effect. PreADMET and Dragon software was used for in silico prediction of pharmacokinetics and pharmacodynamics of SMe1EC2M3. Forced swim test was used to evaluate its antidepressant-like effects. Extracellular in vivo electrophysiology was used to assess 5-HT, norepinephrine, and dopamine reuptake inhibition efficacy of SMe1EC2M3. PreADMET predicted reasonable intestinal absorption, plasma protein binding, and blood-brain permeability for SMe1EC2M3. Dragon forecasted its efficiency as an antidepressant. Using behavioral measurements, it was found that SMe1EC2M3 decreased immobility time and increase swimming time during the forced swim test (FST). Electrophysiological investigations showed that SMe1EC2M3 dose-dependently suppressed the excitability of 5-HT neurons of the dorsal raphe nucleus (DRN), norepinephrine neurons of the locus coeruleus (LC), and dopamine neurons of the ventral tegmental area (VTA). The SMe1EC2M3-induced suppression of 5-HT, norepinephrine, and dopamine neurons was reversed by the antagonists of serotonin-1A (5-HT1A; WAY100135), α-2 adrenergic (α2, yohimbine), and dopamine-2 receptors (D2, haloperidol), respectively. We conclude that SMe1EC2M3 is prospective triple 5-HT, norepinephrine, and dopamine reuptake inhibitor with antidepressant-like properties, however future studies should be performed to complete the pharmacological profiling of this compound.

Doc2b Ca2+ binding site mutants enhance synaptic release at rest at the expense of sustained synaptic strength.

Communication between neurons involves presynaptic neurotransmitter release which can be evoked by action potentials or occur spontaneously as a result of stochastic vesicle fusion. The Ca2+-binding double C2 proteins Doc2a and -b were implicated in spontaneous and asynchronous evoked release, but the mechanism remains unclear. Here, we compared wildtype Doc2b with two Ca2+ binding site mutants named DN and 6A, previously classified as gain- and loss-of-function mutants. They carry the substitutions D218,220N or D163,218,220,303,357,359A respectively. We found that both mutants bound phospholipids at low Ca2+ concentrations and were membrane-associated in resting neurons, thus mimicking a Ca2+-activated state. Their overexpression in hippocampal primary cultured neurons had similar effects on spontaneous and evoked release, inducing high mEPSC frequencies and increased short-term depression. Together, these data suggest that the DN and 6A mutants both act as gain-of-function mutants at resting conditions.

Early life stress: update on neurophysiologic effects and treatment.

PURPOSE OF REVIEW: Recent research on childhood trauma has focused on the effects of in-utero and early life stress (ELS) as well as improving access to care. This review includes the previous year's clinically relevant research with attention to gaps that require further research that should improve patient care. RECENT FINDINGS: The current article focuses on the latest understanding of ELS effects on the neuroendocrine, inflammatory, immune, and neurologic systems, as well as epigenetic effects with a focus on research examining sex-specific differences. Resilience and innovative treatment delivery models are reviewed with emphasis on integrated care models and technology-based treatments. SUMMARY: The findings reviewed point toward clinically relevant research avenues. The call for more and better treatment options can only be realized with a better understanding of ELS effects. There is a specific need for more in depth exploration and application of sex-specific differences as well as an examination of the effects of age of onset and chronicity of stressors. New developments in the delivery of interventions and treatment allow the potential to provide broader early access to care.

Ensemble inhibition and excitation in the human cortex: An Ising-model analysis with uncertainties.

The pairwise maximum entropy model, also known as the Ising model, has been widely used to analyze the collective activity of neurons. However, controversy persists in the literature about seemingly inconsistent findings, whose significance is unclear due to lack of reliable error estimates. We therefore develop a method for accurately estimating parameter uncertainty based on random walks in parameter space using adaptive Markov-chain Monte Carlo after the convergence of the main optimization algorithm. We apply our method to the activity patterns of excitatory and inhibitory neurons recorded with multielectrode arrays in the human temporal cortex during the wake-sleep cycle. Our analysis shows that the Ising model captures neuronal collective behavior much better than the independent model during wakefulness, light sleep, and deep sleep when both excitatory (E) and inhibitory (I) neurons are modeled; ignoring the inhibitory effects of I neurons dramatically overestimates synchrony among E neurons. Furthermore, information-theoretic measures reveal that the Ising model explains about 80-95% of the correlations, depending on sleep state and neuron type. Thermodynamic measures show signatures of criticality, although we take this with a grain of salt as it may be merely a reflection of long-range neural correlations.

Direct assessment of presynaptic modulation of cortico-striatal glutamate release in a Huntington's disease mouse model.

Glutamate is the main excitatory neurotransmitter in the brain, and impairments in its signaling are associated with many neurological disorders, including Huntington's disease (HD). Previous studies in HD mouse models demonstrate altered glutamate receptor distribution and signaling at cortico-striatal synapses, and some studies suggest that glutamate release is altered; however, traditional methods to study synaptic glutamate release are indirect or have poor temporal resolution. Here we utilize iGluSnFR, a modified green fluorescent protein reporter for real-time imaging of glutamate transmission, to study presynaptic modulation of cortical glutamate release in the striatum of the YAC128 HD mouse model. We determined that iGluSnFR can be used to accurately measure short- and long-term changes in glutamate release caused by modulation of extracellular Ca2+ levels, activation of presynaptic receptors, and high-frequency stimulation (HFS) protocols. We also confirmed a difference in the expression of HFS-induced long-term depression in YAC128. Together, this research demonstrates the utility of iGluSnFR in studying presynaptic modulation of glutamate release in healthy mice and disease models that display impairments in glutamate signaling. NEW & NOTEWORTHY We use iGluSnFR to directly assess presynaptic modulation of cortico-striatal glutamate release in brain slice and compare changes in glutamate release between wild type and a Huntington's disease mouse model, YAC128. We observed reductions in glutamate release after low extracellular Ca2+ and activation of various presynaptic receptors. We also demonstrate a presynaptic mechanism of reduced glutamate release in high-frequency stimulation-induced long-term depression and show this to be altered in YAC128.

The Additional Value of PET in the Assessment of Cerebral Small Vessel Disease.

The diagnosis of cerebral small vessel disease (SVD) is difficult because there is no consensus on clinical criteria, and therefore imaging is important for diagnosis. Most patients undergo brain imaging by CT, which is able to detect ischemic strokes, hemorrhages, and brain atrophy and may also indicate white matter changes. MRI remains the key neuroimaging modality and is preferred to CT in vascular cognitive impairment (VCI) because it has higher sensitivity and specificity for detecting pathologic changes. These modalities for imaging morphology permit detection of vascular lesions traditionally attributed to VCI in subcortical areas of the brain, single infarction or lacunes in strategic areas (thalamus or angular gyrus), or large cortical-subcortical lesions reaching a critical threshold of tissue loss. In SVD, multiple punctuate or confluent lesions can be seen in the white matter by MRI and were called leukoaraiosis. Another major neuroimaging finding of SVD in VCI are microhemorrhages. However, whereas CT and MRI are able to detect morphologic lesions, these modalities cannot determine functional consequences of the underlying pathologic changes. PET can support the clinical diagnosis by visualizing cerebral functions in typically affected brain regions. In SVD, 18F-FDG PET can clearly differentiate scattered areas of focal cortical and subcortical hypometabolism that differ from the typical metabolic pattern seen in Alzheimer dementia (AD) with marked hypometabolism affecting the association areas. Additional PET tracers can further support the diagnosis of a type of dementia and also yield information on the underlying pathophysiology.

Altering gain of the infralimbic-to-accumbens shell circuit alters economically dissociable decision-making algorithms.

The nucleus accumbens shell (NAcSh) is involved in reward valuation. Excitatory projections from infralimbic cortex (IL) to NAcSh undergo synaptic remodeling in rodent models of addiction and enable the extinction of disadvantageous behaviors. However, how the strength of synaptic transmission of the IL-NAcSh circuit affects decision-making information processing and reward valuation remains unknown, particularly because these processes can conflict within a given trial and particularly given recent data suggesting that decisions arise from separable information-processing algorithms. The approach of many neuromodulation studies is to disrupt information flow during on-going behaviors; however, this limits the interpretation of endogenous encoding of computational processes. Furthermore, many studies are limited by the use of simple behavioral tests of value which are unable to dissociate neurally distinct decision-making algorithms. We optogenetically altered the strength of synaptic transmission between glutamatergic IL-NAcSh projections in mice trained on a neuroeconomic task capable of separating multiple valuation processes. We found that induction of long-term depression in these synapses produced lasting changes in foraging processes without disrupting deliberative processes. Mice displayed inflated reevaluations to stay when deciding whether to abandon continued reward-seeking investments but displayed no changes during initial commitment decisions. We also developed an ensemble-level measure of circuit-specific plasticity that revealed individual differences in foraging valuation tendencies. Our results demonstrate that alterations in projection-specific synaptic strength between the IL and the NAcSh are capable of augmenting self-control economic valuations within a particular decision-making modality and suggest that the valuation mechanisms for these multiple decision-making modalities arise from different circuits.

Concurrence of form and function in developing networks and its role in synaptic pruning.

A fundamental question in neuroscience is how structure and function of neural systems are related. We study this interplay by combining a familiar auto-associative neural network with an evolving mechanism for the birth and death of synapses. A feedback loop then arises leading to two qualitatively different types of behaviour. In one, the network structure becomes heterogeneous and dissasortative, and the system displays good memory performance; furthermore, the structure is optimised for the particular memory patterns stored during the process. In the other, the structure remains homogeneous and incapable of pattern retrieval. These findings provide an inspiring picture of brain structure and dynamics that is compatible with experimental results on early brain development, and may help to explain synaptic pruning. Other evolving networks-such as those of protein interactions-might share the basic ingredients for this feedback loop and other questions, and indeed many of their structural features are as predicted by our model.

Analytical modelling of temperature effects on an AMPA-type synapse.

It was previously reported, that temperature may significantly influence neural dynamics on the different levels of brain function. Thus, in computational neuroscience, it would be useful to make models scalable for a wide range of various brain temperatures. However, lack of experimental data and an absence of temperature-dependent analytical models of synaptic conductance does not allow to include temperature effects at the multi-neuron modeling level. In this paper, we propose a first step to deal with this problem: A new analytical model of AMPA-type synaptic conductance, which is able to incorporate temperature effects in low-frequency stimulations. It was constructed based on Markov model description of AMPA receptor kinetics using the set of coupled ODEs. The closed-form solution for the set of differential equations was found using uncoupling assumption (introduced in the paper) with few simplifications motivated both from experimental data and from Monte Carlo simulation of synaptic transmission. The model may be used for computationally efficient and biologically accurate implementation of temperature effects on AMPA receptor conductance in large-scale neural network simulations. As a result, it may open a wide range of new possibilities for researching the influence of temperature on certain aspects of brain functioning.

What Is the Evidence for "Food Addiction?" A Systematic Review.

The diagnostic construct of "food addiction" is a highly controversial subject. The current systematic review is the first to evaluate empirical studies examining the construct of "food addiction" in humans and animals. Studies were included if they were quantitative, peer-reviewed, and in the English language. The 52 identified studies (35 articles) were qualitatively assessed to determine the extent to which their findings indicated the following addiction characteristics in relation to food: brain reward dysfunction, preoccupation, risky use, impaired control, tolerance/withdrawal, social impairment, chronicity, and relapse. Each pre-defined criterion was supported by at least one study. Brain reward dysfunction and impaired control were supported by the largest number of studies (n = 21 and n = 12, respectively); whereas risky use was supported by the fewest (n = 1). Overall, findings support food addiction as a unique construct consistent with criteria for other substance use disorder diagnoses. The evidence further suggests that certain foods, particularly processed foods with added sweeteners and fats, demonstrate the greatest addictive potential. Though both behavioral and substance-related factors are implicated in the addictive process, symptoms appear to better fit criteria for substance use disorder than behavioral addiction. Future research should explore social/role impairment, preoccupation, and risky use associated with food addiction and evaluate potential interventions for prevention and treatment.

A Fast Algorithm for Analysis of Molecular Communication in Artificial Synapse.

In this paper, we analyze molecular communications (MCs) in a proposed artificial synapse (AS), whose main difference from biological synapses (BSs) is that it is closed, i.e., transmitter molecules cannot diffuse out from AS. Such a setup has both advantages and disadvantages. Besides higher structural stability, being closed, AS never runs out of transmitters. Thus, MC in AS is disconnected from outer environment, which is very desirable for possible intra-body applications. On the other hand, clearance of transmitters from AS has to be achieved by transporter molecules on the presynaptic membrane of AS. Except from these differences, rest of AS content is taken to be similar to that of a glutamatergic BS. Furthermore, in place of commonly used Monte Carlo-based random walk experiments, we derive a deterministic algorithm that attacks for expected values of desired parameters such as evolution of receptor states. To assess validity of our algorithm, we compare its results with average results of an ensemble of Monte Carlo experiments, which shows near exact match. Moreover, our approach requires significantly less amount of computation compared with Monte Carlo approach, making it useful for parameter space exploration necessary for optimization in design of possible MC devices, including but not limited to AS. Results of our algorithm are presented in case of single quantal release only, and they support that MC in closed AS with elevated uptake has similar properties to that in BS. In particular, similar to glutamatergic BSs, the quantal size and the density of receptors are found to be main sources of synaptic plasticity. On the other hand, the proposed model of AS is found to have slower decaying transients of receptor states than BSs, especially desensitized ones, which is due to prolonged clearance of transmitters from AS.

Non-invasive Assessment of Changes in Corticomotoneuronal Transmission in Humans.

The corticospinal pathway is the major pathway connecting the brain with the muscles and is therefore highly relevant for movement control and motor learning. There exists a number of noninvasive electrophysiological methods investigating the excitability and plasticity of this pathway. However, most methods are based on quantification of compound potentials and neglect that the corticospinal pathway consists of many different connections that are more or less direct. Here, we present a method that allows testing excitability of different fractions of the corticospinal transmission. This so called H-reflex conditioning technique allows one to assess excitability of the fastest (monosynaptic) and also polysynaptic corticospinal pathways. Furthermore, by using two different stimulation sites, the motor cortex and the cervicomedullary junction, it allows not only differentiation between cortical and spinal effects but also assessment of transmission at the corticomotoneural synapse. In this manuscript, we describe how this method can be used to assess corticomotoneural transmission after low-frequency repetitive transcranial magnetic stimulation, a method that was previously shown to reduce excitability of cortical cells. Here we demonstrate that not only cortical cells are affected by this repetitive stimulation but also transmission at the corticomotoneuronal synapse at the spinal level. This finding is important for the understanding of basic mechanisms and sites of neuroplasticity. Besides investigation of basic mechanisms, the H-reflex conditioning technique may be applied to test changes in corticospinal transmission following behavioral (e.g., training) or therapeutic interventions, pathology or aging and therefore allows a better understanding of neural processes that underlie movement control and motor learning.

Diffusion-Based Model for Synaptic Molecular Communication Channel.

Computational methods have been extensively used to understand the underlying dynamics of molecular communication methods employed by nature. One very effective and popular approach is to utilize a Monte Carlo simulation. Although it is very reliable, this method can have a very high computational cost, which in some cases renders the simulation impractical. Therefore, in this paper, for the special case of an excitatory synaptic molecular communication channel, we present a novel mathematical model for the diffusion and binding of neurotransmitters that takes into account the effects of synaptic geometry in 3-D space and re-absorption of neurotransmitters by the transmitting neuron. Based on this model we develop a fast deterministic algorithm, which calculates expected value of the output of this channel, namely, the amplitude of excitatory postsynaptic potential (EPSP), for given synaptic parameters. We validate our algorithm by a Monte Carlo simulation, which shows total agreement between the results of the two methods. Finally, we utilize our model to quantify the effects of variation in synaptic parameters, such as position of release site, receptor density, size of postsynaptic density, diffusion coefficient, uptake probability, and number of neurotransmitters in a vesicle, on maximum number of bound receptors that directly affect the peak amplitude of EPSP.

PAR1 activation induces rapid changes in glutamate uptake and astrocyte morphology.

The G-protein coupled, protease-activated receptor 1 (PAR1) is a membrane protein expressed in astrocytes. Fine astrocytic processes are in tight contact with neurons and blood vessels and shape excitatory synaptic transmission due to their abundant expression of glutamate transporters. PAR1 is proteolytically-activated by bloodstream serine proteases also involved in the formation of blood clots. PAR1 activation has been suggested to play a key role in pathological states like thrombosis, hemostasis and inflammation. What remains unclear is whether PAR1 activation also regulates glutamate uptake in astrocytes and how this shapes excitatory synaptic transmission among neurons. Here we show that, in the mouse hippocampus, PAR1 activation induces a rapid structural re-organization of the neuropil surrounding glutamatergic synapses, which is associated with faster clearance of synaptically-released glutamate from the extracellular space. This effect can be recapitulated using realistic 3D Monte Carlo reaction-diffusion simulations, based on axial scanning transmission electron microscopy (STEM) tomography reconstructions of excitatory synapses. The faster glutamate clearance induced by PAR1 activation leads to short- and long-term changes in excitatory synaptic transmission. Together, these findings identify PAR1 as an important regulator of glutamatergic signaling in the hippocampus and a possible target molecule to limit brain damage during hemorrhagic stroke.