Publications by authors named "Laurent Groc"

91 Publications

NMDA receptor membrane dynamics tunes the firing pattern of midbrain dopaminergic neurons.

J Physiol 2021 Mar 2. Epub 2021 Mar 2.

Interdisciplinary Institute for Neuroscience, Université de Bordeaux, UMR 5297, Bordeaux, F-33000, France.

Key Points: NMDA receptors (NMDARs) expressed by dopamine neurons of the ventral tegmental area (VTA) play a central role in glutamate synapse plasticity, neuronal firing and adaptative behaviours. The NMDAR surface dynamics shapes synaptic adaptation in hippocampal networks, as well as associative memory. We investigated the basic properties and role of the NMDAR surface dynamics on cultured mesencephalic and VTA dopamine neurons in rodents. Using a combination of single molecule imaging and electrophysiological recordings, we demonstrate that NMDARs are highly diffusive at the surface of mesencephalic dopamine neurons. Unexpectedly, the NMDAR membrane dynamics per se regulates the firing pattern of VTA dopaminergic neurons, probably through a functional interplay between NMDARs receptors and small-conductance calcium-dependent potassium (SK) channels.

Abstract: Midbrain dopaminergic (DA) neurons play a central role in major physiological brain functions, and their dysfunctions have been associated with neuropsychiatric diseases. The activity of midbrain DA neurons is controlled by ion channels and neurotransmitter receptors, such as the glutamate NMDA receptor (NMDAR) and small-conductance calcium-dependent potassium (SK) channels. However, the cellular mechanisms through which these channels tune the firing pattern of midbrain DA neurons remain unclear. Here, we investigated whether the surface dynamics and distribution of NMDARs tunes the firing pattern of midbrain DA neurons. Using a combination of single molecule imaging and electrophysiological recordings, we report that NMDARs are highly diffusive at the surface of cultured midbrain DA neurons from rodents and humans. Reducing acutely the NMDAR membrane dynamics, which leaves the ionotropic function of the receptor intact, robustly altered the firing pattern of midbrain DA neurons without altering synaptic glutamatergic transmission. The reduction of NMDAR surface dynamics reduced apamin (SK channel blocker)-induced firing change and the distribution of SK3 channels in DA neurons. Together, these data show that the surface dynamics of NMDAR, and not solely its ionotropic function, tune the firing pattern of midbrain DA neurons partly through a functional interplay with SK channel function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/JP281104DOI Listing
March 2021

Relationship Between Serum NMDA Receptor Antibodies and Response to Antipsychotic Treatment in First-Episode Psychosis.

Biol Psychiatry 2020 Nov 24. Epub 2020 Nov 24.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, United Kingdom; South London and Maudsley NHS Foundation Trust, University College London, London, United Kingdom.

Background: When psychosis develops in NMDA receptor (NMDAR) antibody encephalitis, it usually has an acute or subacute onset, and antipsychotic treatment may be ineffective and associated with adverse effects. Serum NMDAR antibodies have been reported in a minority of patients with first-episode psychosis (FEP), but their role in psychosis onset and response to antipsychotic treatment is unclear.

Methods: Sera from 387 patients with FEP (duration of psychosis <2 years, minimally or never treated with antipsychotics) undergoing initial treatment with amisulpride as part of the OPTiMiSE (Optimization of Treatment and Management of Schizophrenia in Europe) trial (ClinicalTrials.gov number NCT01248195) were tested for NMDAR IgG antibodies using a live cell-based assay. Symptom severity was assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impressions Scale at baseline and again after 4 weeks of treatment with amisulpride.

Results: At baseline, 15 patients were seropositive for NMDAR antibodies and 372 were seronegative. The seropositive patients had similar symptom profiles and demographic features to seronegative patients but a shorter duration of psychosis (median 1.5 vs. 4.0 months; p = .031). Eleven seropositive and 284 seronegative patients completed 4 weeks of amisulpride treatment: after treatment, there was no between-groups difference in improvement in Positive and Negative Syndrome Scale scores or in the frequency of adverse medication effects.

Conclusions: These data suggest that in FEP, NMDAR antibody seropositivity alone is not an indication for using immunotherapy instead of antipsychotic medications. Further studies are required to establish what proportion of patients with FEP who are NMDAR antibody seropositive have coexisting cerebrospinal fluid inflammatory changes or other paraclinical evidence suggestive of a likely benefit from immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2020.11.014DOI Listing
November 2020

Regulation of membrane NMDA receptors by dynamics and protein interactions.

J Cell Biol 2021 Jan;220(1)

Université de Bordeaux, Centre National de la Recherche Scientifique, Interdisciplinary Institute for Neuroscience, Unité Mixte de Recherche 5297, Bordeaux, France.

Understanding neurotransmitter system crosstalk in the brain is a major challenge in neurobiology. Several intracellular and genomic cascades have been identified in this crosstalk. However, the discovery that neurotransmitter receptors are highly diffusive in the plasma membrane of neurons, where they form heterocomplexes with other proteins, has profoundly changed our view of neurotransmitter signaling. Here, we review new insights into neurotransmitter crosstalk at the plasma membrane. We focus on the membrane organization and interactome of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR) that plays a central role in excitatory synaptic and network physiology and is involved in the etiology of several major neuropsychiatric disorders. The nanoscale organization and dynamics of NMDAR is a key regulatory process for glutamate synapse transmission, plasticity, and crosstalk with other neurotransmitter systems, such as the monoaminergic ones. The plasma membrane appears to be a prime regulatory compartment for spatial and temporal crosstalk between neurotransmitter systems in the healthy and diseased brain. Understanding the molecular mechanisms regulating membrane neurotransmitter receptor crosstalk will likely open research avenues for innovative therapeutical strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1083/jcb.202006101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754687PMC
January 2021

Autoimmunity and NMDA receptor in brain disorders: Where do we stand?

Neurobiol Dis 2021 01 6;147:105161. Epub 2020 Nov 6.

Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France. Electronic address:

Over the past decades, the identification of autoimmune encephalitis in which patients express autoantibodies directed against neurotransmitter receptors has generated great hope to shed new light on the molecular mechanisms underpinning neurological and psychiatric conditions. Among these autoimmune encephalitides, the discovery of autoantibodies directed against the glutamatergic NMDA receptor (NMDAR-Ab), in the anti-NMDAR encephalitis, has provided some key information on how complex neuropsychiatric symptoms can be caused by a deficit in NMDAR signalling. Yet, NMDAR-Abs have also been detected in several neurological and psychiatric conditions, as well as in healthy individuals. In addition, these various NMDAR-Abs appear to have different molecular properties and pathogenicities onto receptors and synaptic functions. Here, we discuss the current view on the variety of NMDAR-Abs and, in particular, how these autoantibodies can lead to receptor dysfunction in neuronal networks. Since our mechanistic understanding on patients' NMDAR-Abs is still in its infancy, several complementary processes can be proposed and further in-depth molecular and cellular investigations will surely reveal key insights. Autoantibodies represent a great opportunity to gain knowledge on the etiology of neuropsychiatric disorders and pave the way for innovative therapeutic strategies. ONE SENTENCE SUMMARY: Current view on patients' autoantibody against NMDAR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2020.105161DOI Listing
January 2021

Distance-dependent regulation of NMDAR nanoscale organization along hippocampal neuron dendrites.

Proc Natl Acad Sci U S A 2020 09 14;117(39):24526-24533. Epub 2020 Sep 14.

Interdisciplinary Institute for Neuroscience, University of Bordeaux, UMR 5297, 33076 Bordeaux, France;

Hippocampal pyramidal neurons are characterized by a unique arborization subdivided in segregated dendritic domains receiving distinct excitatory synaptic inputs with specific properties and plasticity rules that shape their respective contributions to synaptic integration and action potential firing. Although the basal regulation and plastic range of proximal and distal synapses are known to be different, the composition and nanoscale organization of key synaptic proteins at these inputs remains largely elusive. Here we used superresolution imaging and single nanoparticle tracking in rat hippocampal neurons to unveil the nanoscale topography of native GluN2A- and GluN2B-NMDA receptors (NMDARs)-which play key roles in the use-dependent adaptation of glutamatergic synapses-along the dendritic arbor. We report significant changes in the nanoscale organization of GluN2B-NMDARs between proximal and distal dendritic segments, whereas the topography of GluN2A-NMDARs remains similar along the dendritic tree. Remarkably, the nanoscale organization of GluN2B-NMDARs at proximal segments depends on their interaction with calcium/calmodulin-dependent protein kinase II (CaMKII), which is not the case at distal segments. Collectively, our data reveal that the nanoscale organization of NMDARs changes along dendritic segments in a subtype-specific manner and is shaped by the interplay with CaMKII at proximal dendritic segments, shedding light on our understanding of the functional diversity of hippocampal glutamatergic synapses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1922477117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533699PMC
September 2020

Consequences of NMDA receptor deficiency can be rescued in the adult brain.

Mol Psychiatry 2020 Aug 17. Epub 2020 Aug 17.

Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.

N-methyl-D-aspartate receptors (NMDARs) are required to shape activity-dependent connections in the developing and adult brain. Impaired NMDAR signalling through genetic or environmental insults causes a constellation of neurodevelopmental disorders that manifest as intellectual disability, epilepsy, autism, or schizophrenia. It is not clear whether the developmental impacts of NMDAR dysfunction can be overcome by interventions in adulthood. This question is paramount for neurodevelopmental disorders arising from mutations that occur in the GRIN genes, which encode NMDAR subunits, and the broader set of mutations that disrupt NMDAR function. We developed a mouse model where a congenital loss-of-function allele of Grin1 can be restored to wild type by gene editing with Cre recombinase. Rescue of NMDARs in adult mice yields surprisingly robust improvements in cognitive functions, including those that are refractory to treatment with current medications. These results suggest that neurodevelopmental disorders arising from NMDAR deficiency can be effectively treated in adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-020-00859-4DOI Listing
August 2020

Synucleinopathy alters nanoscale organization and diffusion in the brain extracellular space through hyaluronan remodeling.

Nat Commun 2020 07 10;11(1):3440. Epub 2020 Jul 10.

Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33076, Bordeaux, France.

In recent years, exploration of the brain extracellular space (ECS) has made remarkable progress, including nanoscopic characterizations. However, whether ECS precise conformation is altered during brain pathology remains unknown. Here we study the nanoscale organization of pathological ECS in adult mice under degenerative conditions. Using electron microscopy in cryofixed tissue and single nanotube tracking in live brain slices combined with super-resolution imaging analysis, we find enlarged ECS dimensions and increased nanoscale diffusion after α-synuclein-induced neurodegeneration. These animals display a degraded hyaluronan matrix in areas close to reactive microglia. Furthermore, experimental hyaluronan depletion in vivo reduces dopaminergic cell loss and α-synuclein load, induces microgliosis and increases ECS diffusivity, highlighting hyaluronan as diffusional barrier and local tissue organizer. These findings demonstrate the interplay of ECS, extracellular matrix and glia in pathology, unraveling ECS features relevant for the α-synuclein propagation hypothesis and suggesting matrix manipulation as a disease-modifying strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17328-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351768PMC
July 2020

Linking glutamate receptor movements and synapse function.

Science 2020 06;368(6496)

Interdisciplinary Institute for NeuroScience, CNRS, UMR 5297, Centre Broca Nouvelle-Aquitaine, 146, rue Léo-Saignat, 33076 Bordeaux, France.

Regulation of neurotransmitter receptor content at synapses is achieved through a dynamic equilibrium between biogenesis and degradation pathways, receptor stabilization at synaptic sites, and receptor trafficking in and out synapses. In the past 20 years, the movements of receptors to and from synapses have emerged as a series of highly regulated processes that mediate postsynaptic plasticity. Our understanding of the properties and roles of receptor movements has benefited from technological advances in receptor labeling and tracking capacities, as well as from new methods to interfere with their movements. Focusing on two key glutamatergic receptors, we review here our latest understanding of the characteristics of receptor movements and their role in tuning the efficacy of synaptic transmission in health and brain disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aay4631DOI Listing
June 2020

Fluorescent sp Defect-Tailored Carbon Nanotubes Enable NIR-II Single Particle Imaging in Live Brain Slices at Ultra-Low Excitation Doses.

Sci Rep 2020 03 24;10(1):5286. Epub 2020 Mar 24.

Université de Bordeaux, Laboratoire Photonique Numérique et Nanosciences, UMR 5298, 33400, Talence, France.

Cellular and tissue imaging in the second near-infrared window (NIR-II, ~1000-1350 nm) is advantageous for in vivo studies because of low light extinction by biological constituents at these wavelengths. However, deep tissue imaging at the single molecule sensitivity has not been achieved in the NIR-II window due to lack of suitable bio-probes. Single-walled carbon nanotubes have emerged as promising near-infrared luminescent molecular bio-probes; yet, their inefficient photoluminescence (quantum yield ~1%) drives requirements for sizeable excitation doses (~1-10 kW/cm) that are significantly blue-shifted from the NIR-II region (<850 nm) and may thus ultimately compromise live tissue. Here, we show that single nanotube imaging can be achieved in live brain tissue using ultralow excitation doses (~0.1 kW/cm), an order of magnitude lower than those currently used. To accomplish this, we synthesized fluorescent sp-defect tailored (6,5) carbon nanotubes which, when excited at their first order excitonic transition (~985 nm) fluoresce brightly at ~1160 nm. The biocompatibility of these functionalized nanotubes, which are wrapped by encapsulation agent (phospholipid-polyethylene glycol), is demonstrated using standard cytotoxicity assays. Single molecule photophysical studies of these biocompatible nanotubes allowed us to identify the optimal luminescence properties in the context of biological imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-62201-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093457PMC
March 2020

Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin.

Lancet Psychiatry 2020 01 24;7(1):93-108. Epub 2019 Oct 24.

Department of Psychiatry and Psychotherapy II, Ulm University, Bezirkskrankenhaus Günzburg, Günzburg, Germany.

There is increasing recognition in the neurological and psychiatric literature of patients with so-called isolated psychotic presentations (ie, with no, or minimal, neurological features) who have tested positive for neuronal autoantibodies (principally N-methyl-D-aspartate receptor antibodies) and who have responded to immunotherapies. Although these individuals are sometimes described as having atypical, mild, or attenuated forms of autoimmune encephalitis, some authors feel that that these cases are sufficiently different from typical autoimmune encephalitis to establish a new category of so-called autoimmune psychosis. We briefly review the background, discuss the existing evidence for a form of autoimmune psychosis, and propose a novel, conservative approach to the recognition of possible, probable, and definite autoimmune psychoses for use in psychiatric practice. We also outline the investigations required and the appropriate therapeutic approaches, both psychiatric and immunological, for probable and definite cases of autoimmune psychoses, and discuss the ethical issues posed by this challenging diagnostic category.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2215-0366(19)30290-1DOI Listing
January 2020

Human Autoantibodies Against N-Methyl-D-Aspartate Receptor Modestly Alter Dopamine D1 Receptor Surface Dynamics.

Front Psychiatry 2019 13;10:670. Epub 2019 Sep 13.

Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France.

Circulating autoantibodies directed against extracellular domains of the glutamatergic N-methyl-D-aspartate receptors (NMDAR-Ab) elicit psychotic symptoms in humans and behavioral deficits in animal models. Recent advances suggest that NMDAR-Ab exert their pathogenic action by altering the trafficking of NMDAR, which results in a synaptic NMDAR hypofunction consistent with the consensual glutamatergic hypothesis of psychotic disorders. Yet, dysfunction in the dopaminergic signaling is also proposed to be at the core of psychotic disorders. Since NMDAR and dopamine D1 receptors (D1R) form membrane signaling complexes, we investigated whether NMDAR-Ab purified from patients with NMDAR-encephalitis or schizophrenia impaired D1R surface dynamics. As previous data demonstrated that NMDAR-Ab, at least from NMDAR-encephalitis patients, mainly bind to hippocampal NMDAR, we used single nanoparticle imaging to track D1R specifically at the surface of hippocampal neurons that were exposed to either purified G type immunoglobulins (IgGs) from NMDAR-Ab seropositive patients suffering from NMDAR-encephalitis or schizophrenia, or control IgGs from healthy NMDAR-Ab seropositive or seronegative subjects. We report that overnight incubation with NMDAR-Ab from patients, but not from healthy carriers, decreased the surface dynamics of D1R compared with NMDAR-Ab seronegative IgGs. This decrease was abolished, and even reversed, in D1R mutant that cannot physically interact with NMDAR. Overall, our data indicate that NMDAR-Ab from patients with psychotic symptoms alter the trafficking of D1R, likely through the surface crosstalk between NMDAR and D1R.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyt.2019.00670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754069PMC
September 2019

Aquaporin-4 Surface Trafficking Regulates Astrocytic Process Motility and Synaptic Activity in Health and Autoimmune Disease.

Cell Rep 2019 06;27(13):3860-3872.e4

Interdisciplinary Institute for NeuroSciences, CNRS UMR 5297, 33077 Bordeaux, France; Université de Bordeaux, 33077 Bordeaux, France. Electronic address:

Astrocytes constantly adapt their ramified morphology in order to support brain cell assemblies. Such plasticity is partly mediated by ion and water fluxes, which rely on the water channel aquaporin-4 (AQP4). The mechanism by which this channel locally contributes to process dynamics has remained elusive. Using a combination of single-molecule and calcium imaging approaches, we here investigated in hippocampal astrocytes the dynamic distribution of the AQP4 isoforms M1 and M23. Surface AQP4-M1 formed small aggregates that contrast with the large AQP4-M23 clusters that are enriched near glutamatergic synapses. Strikingly, stabilizing surface AQP4-M23 tuned the motility of astrocyte processes and favors glutamate synapse activity. Furthermore, human autoantibodies directed against AQP4 from neuromyelitis optica (NMO) patients impaired AQP4-M23 dynamic distribution and, consequently, astrocyte process and synaptic activity. Collectively, it emerges that the membrane dynamics of AQP4 isoform regulate brain cell assemblies in health and autoimmune brain disease targeting AQP4.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2019.05.097DOI Listing
June 2019

Surface trafficking of neurotransmitter receptors: From cultured neurons to intact brain preparations.

Neuropharmacology 2020 06 17;169:107642. Epub 2019 May 17.

Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000, Bordeaux, France; CNRS, IINS UMR 5297, 33000, Bordeaux, France. Electronic address:

Over the last decade, developments in single molecule imaging have changed our vision of synaptic physiology. By providing high spatio-temporal resolution maps of the molecular actors of neurotransmissions, these techniques have revealed that pre- and post-synaptic proteins are not randomly distributed but precisely organized at the nanoscale, and that this specific organization is dynamically regulated. At the centre of synaptic transmissions, neurotransmitter receptors have been shown to form nanodomains at synapses and to dynamically move in and out of these confinement areas through lateral diffusion within the membrane plane on millisecond timescales, thereby directly contributing to the regulation of synaptic transmission and plasticity. Since the vast majority of these discoveries originated from observations made on dissociated neurons lacking several features of brain tissue (e.g. three-dimensional organization, tissue density), they were initially considered with caution. However, the recent implementation of single-particle tracking (SPT) approaches in cultured and acute brain preparations confirmed that early findings on the dynamic properties of receptors at the surface of neurons can be extended to more physiological conditions. Taking example of dopamine D1 and NMDA glutamate receptors we here review our current knowledge of the features of neurotransmitter receptor surface diffusion in intact brain tissue. Through detailed comparison with cultured neurons, we also discuss how these biophysical properties are influenced by the complexity of the extracellular environment. This article is part of the special issue entitled 'Mobility and trafficking of neuronal membrane proteins'.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2019.05.019DOI Listing
June 2020

Role of CX3CR1 Signaling on the Maturation of GABAergic Transmission and Neuronal Network Activity in the Neonate Hippocampus.

Neuroscience 2019 May 12;406:186-201. Epub 2019 Mar 12.

Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, Centre Broca Nouvelle-Aquitaine, 146 rue Léo Saignat, CS 61292 Case 130, 33076 Bordeaux Cedex, France; CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, Centre Broca Nouvelle-Aquitaine, 146 rue Léo Saignat, CS 61292 Case 130, 33076 Bordeaux Cedex, France. Electronic address:

In the developing brain, microglial cells play an important role in shaping neuronal circuits. These immune cells communicate with neurons through fractalkine (CX3CL1), a neuronal cytokine that acts on microglial CX3CR1 receptor. Among various functions, this signaling pathway has been implicated in the postnatal maturation of glutamatergic synapses. Although microglial cells are present in the neonate hippocampus when GABA receptor-mediated synaptic transmission and synchronized oscillatory events take place, it remains unknown whether microglial cells tune the establishment of these activities. Using CX3CR1-deficient mice and electrophysiological means, we investigated in CA3 pyramidal neurons the role of the fractalkine signaling in the maturation of GABA receptor-mediated synaptic currents and giant depolarizing potentials (GDPs), a network activity important for shaping synaptic connections. In CX3CR1-deficient mice, GABAergic currents were slightly altered, whereas the developmental changes of these currents were comparable with wild-type animals. Despite these minor changes in GABAergic transmission, the GDP frequency was strikingly reduced in CX3CR1-deficient mice compared to wild-type, with no change in the GDP shape and ending period. Collectively, it emerges that, in the neonate hippocampus, the fractalkine signaling pathway tunes GDP activities and is marginally involved in the maturation of GABAergic synapses, suggesting that microglial cells have distinct impact on maturing GABAergic, glutamatergic, and network functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroscience.2019.03.006DOI Listing
May 2019

Nanoscale exploration of the extracellular space in the live brain by combining single carbon nanotube tracking and super-resolution imaging analysis.

Methods 2020 03 9;174:91-99. Epub 2019 Mar 9.

Université de Bordeaux, Laboratoire Photonique Numérique et Nanosciences, UMR 5298, 33400 Talence, France; Institut d'Optique & CNRS, LP2N UMR 5298, 33400 Talence, France. Electronic address:

The brain extracellular space (ECS) is a system of narrow compartments whose intricate nanometric structure has remained elusive until very recently. Understanding such a complex organisation represents a technological challenge that requires a technique able to resolve these nanoscopic spaces and simultaneously characterize their rheological properties. We recently used single-walled carbon nanotubes (SWCNTs) as near-infrared fluorescent probes to map with nanoscale precision the local organization and rheology of the ECS. Here we expand our method by tracking single nanotubes through super-resolution imaging in rat organotypic hippocampal slices and acute brain slices from adult mice, pioneering the exploration of the adult brain ECS at the nanoscale. We found a highly heterogeneous ECS, where local rheological properties can change drastically within few nanometres. Our results suggest differences in local ECS diffusion environments in organotypic slices when compared to adult mouse slices. Data obtained from super-resolved maps of the SWCNT trajectories indicate that ECS widths may vary between brain tissue models, with a looser, less crowded nano-environment in organotypic cultured slices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymeth.2019.03.005DOI Listing
March 2020

Differential Nanoscale Topography and Functional Role of GluN2-NMDA Receptor Subtypes at Glutamatergic Synapses.

Neuron 2018 10 27;100(1):106-119.e7. Epub 2018 Sep 27.

Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France; CNRS, IINS UMR 5297, Bordeaux, France. Electronic address:

NMDA receptors (NMDARs) play key roles in the use-dependent adaptation of glutamatergic synapses underpinning memory formation. In the forebrain, these plastic processes involve the varied contributions of GluN2A- and GluN2B-containing NMDARs that have different signaling properties. Although the molecular machinery of synaptic NMDAR trafficking has been under scrutiny, the postsynaptic spatial organization of these two receptor subtypes has remained elusive. Here, we used super-resolution imaging of NMDARs in rat hippocampal synapses to unveil the nanoscale topography of native GluN2A- and GluN2B-NMDARs. Both subtypes were found to be organized in separate nanodomains that vary over the course of development. Furthermore, GluN2A- and GluN2B-NMDAR nanoscale organizations relied on distinct regulatory mechanisms. Strikingly, the selective rearrangement of GluN2A- and GluN2B-NMDARs, with no overall change in NMDAR current amplitude, allowed bi-directional tuning of synaptic LTP. Thus, GluN2A- and GluN2B-NMDAR nanoscale organizations are differentially regulated and seem to involve distinct signaling complexes during synaptic adaptation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuron.2018.09.012DOI Listing
October 2018

Antidepressive effects of targeting ELK-1 signal transduction.

Nat Med 2018 05 7;24(5):591-597. Epub 2018 May 7.

Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France.

Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement . In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted. The extracellular signal-regulated kinase (ERK) pathway is implicated in mood regulation, but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner , as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-018-0011-0DOI Listing
May 2018

Tracking single membrane targets of human autoantibodies using single nanoparticle imaging.

J Neurosci Methods 2018 07 21;304:76-82. Epub 2018 Apr 21.

CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, Centre Broca Nouvelle-Aquitaine, 146 rue Léo Saignat, CS 61292 Case 130, 33076 Bordeaux Cedex, France; Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, Centre Broca Nouvelle-Aquitaine, 146 rue Léo Saignat, CS 61292 Case 130, 33076 Bordeaux Cedex, France. Electronic address:

Background: Over the past decade, an increasing number of neurological and neuropsychiatric diseases have been associated with the expression of autoantibodies directed against neuronal targets, including neurotransmitter receptors. Although cell-based assays are routinely used in clinics to detect the presence of immunoglobulins, such tests often provide heterogeneous outcomes due to their limited sensitivity, especially at low titers. Thus, there is an urging need for new methods allowing the detection of autoantibodies in seropositive patients that cannot always be clinically distinguished from seronegative ones.

New Method: Here we make a case for single nanoparticle imaging approaches as a highly sensitive antibody detection assay. Through high-affinity interactions between functionalized nanoparticles and autoantibodies that recognize extracellular domains of membrane neuronal targets, single nanoparticle imaging allows a live surface staining of transmembrane proteins and gives access to their surface dynamics.

Results And Comparison With Existing Method(s): We show here that this method is well-suited to detect low titers of purified immunoglobulin G (IgG) from first-episode psychotic patients and demonstrate that these IgG target glutamatergic N-Methyl-d-Aspartate receptors (NMDAR) in live hippocampal neurons. The molecular behaviors of targeted membrane receptors were indistinguishable from those of endogenous GluN1 NMDAR subunit and were virtually independent of the IgG concentration present in the sample contrary to classical cell-based assays.

Conclusions: Single nanoparticle imaging emerges as a real-time sensitive method to detect IgG directed against neuronal surface proteins, which could be used as an additional step to rule out ambiguous seropositivity diagnoses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jneumeth.2018.04.012DOI Listing
July 2018

Molecular Pathogenicity of Anti-NMDA Receptor Autoantibody From Patients With First-Episode Psychosis.

Am J Psychiatry 2018 04;175(4):382-383

From the Interdisciplinary Institute for Neuroscience, Université de Bordeaux, UMR 5297, Bordeaux, France; CNRS, IINS UMR 5297, Bordeaux, France; the Icahn School of Medicine at Mount Sinai, New York; Institut NeuroMyoGène INSERM U1217/CNRS UMR 5310, Université Claude Bernard Lyon 1, Lyon, France; the Department of Psychiatry, Université Paris Est Créteil, Hôpitaux Universitaires Henri Mondor, AP-HP, DHU PePSY, France; the Translational Psychiatry Laboratory, INSERM U955, France; and FondaMental Foundation, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1176/appi.ajp.2017.17091053DOI Listing
April 2018

Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients.

Nat Commun 2017 11 27;8(1):1791. Epub 2017 Nov 27.

Univ. de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33077, Bordeaux, France.

The identification of circulating autoantibodies against neuronal receptors in neuropsychiatric disorders has fostered new conceptual and clinical frameworks. However, detection reliability, putative presence in different diseases and in health have raised questions about potential pathogenic mechanism mediated by autoantibodies. Using a combination of single molecule-based imaging approaches, we here ascertain the presence of circulating autoantibodies against glutamate NMDA receptor (NMDAR-Ab) in about 20% of psychotic patients diagnosed with schizophrenia and very few healthy subjects. NMDAR-Ab from patients and healthy subjects do not compete for binding on native receptor. Strikingly, NMDAR-Ab from patients, but not from healthy subjects, specifically alter the surface dynamics and nanoscale organization of synaptic NMDAR and its anchoring partner the EphrinB2 receptor in heterologous cells, cultured neurons and in mouse brain. Functionally, only patients' NMDAR-Ab prevent long-term potentiation at glutamatergic synapses, while leaving NMDAR-mediated calcium influx intact. We unveil that NMDAR-Ab from psychotic patients alter NMDAR synaptic transmission, supporting a pathogenically relevant role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-017-01700-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702610PMC
November 2017

Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice.

Nat Commun 2017 10 24;8(1):1103. Epub 2017 Oct 24.

INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.

Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology of Fragile X Syndrome (FXS); however, its dysfunction at the sub-cellular level, and related synaptic and cognitive phenotypes are unexplored. Here, we probed the consequences of mGluR5/Homer scaffold disruption for mGluR5 cell-surface mobility, synaptic N-methyl-D-aspartate receptor (NMDAR) function, and behavioral phenotypes in the second-generation Fmr1 knockout (KO) mouse. Using single-molecule tracking, we found that mGluR5 was significantly more mobile at synapses in hippocampal Fmr1 KO neurons, causing an increased synaptic surface co-clustering of mGluR5 and NMDAR. This correlated with a reduced amplitude of synaptic NMDAR currents, a lack of their mGluR5-activated long-term depression, and NMDAR/hippocampus dependent cognitive deficits. These synaptic and behavioral phenomena were reversed by knocking down Homer1a in Fmr1 KO mice. Our study provides a mechanistic link between changes of mGluR5 dynamics and pathological phenotypes of FXS, unveiling novel targets for mGluR5-based therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-017-01191-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653653PMC
October 2017

Dynamics of surface neurotransmitter receptors and transporters in glial cells: Single molecule insights.

Cell Calcium 2017 11 25;67:46-52. Epub 2017 Aug 25.

Interdisciplinary Institute for Neuroscience, CNRS UMR, 5297, Bordeaux, France; University of Bordeaux, Bordeaux, France. Electronic address:

The surface dynamics of neurotransmitter receptors and transporters, as well as ion channels, has been well-documented in neurons, revealing complex molecular behaviour and key physiological functions. However, our understanding of the membrane trafficking and dynamics of the signalling molecules located at the plasma membrane of glial cells is still in its infancy. Yet, recent breakthroughs in the field of glial cells have been obtained using combination of superresolution microscopy, single molecule imaging, and electrophysiological recordings. Here, we review our current knowledge on the surface dynamics of neurotransmitter receptors, transporters and ion channels, in glial cells. It has emerged that the brain cell network activity, synaptic activity, and calcium signalling, regulate the surface distribution and dynamics of these molecules. Remarkably, the dynamics of a given neurotransmitter receptor/transporter at the plasma membrane of a glial cell or neuron is unique, revealing the existence of cell-type specific regulatory pathways. Thus, investigating the dynamics of signalling proteins at the surface of glial cells will likely shed new light on our understanding of glial cell physiology and pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ceca.2017.08.009DOI Listing
November 2017

Hyaluronic acid based extracellular matrix regulates surface expression of GluN2B containing NMDA receptors.

Sci Rep 2017 09 8;7(1):10991. Epub 2017 Sep 8.

Leibniz Institute for Neurobiology, Dept. for Neurochemistry and Molecular Biology, Brenneckestr. 6, Magdeburg, 39118, Germany.

Cortical areas of the juvenile rodent brain display a high degree of structural and functional plasticity, which disappears later in development. Coincident with the decline of plasticity 1) the hyaluronic acid-based extracellular matrix (ECM) of the brain, which stabilizes synapses and neuronal circuit is formed and 2) N-methyl-D-aspartate subtype of ionotropic glutamate receptors (NMDARs) implied in synaptic plasticity switch from mainly GluN2B to GluN2A subunit-containing receptors. Here we tested the hypothesis that ECM influences the NMDAR subunit composition in dissociated neuronal cultures. Experimental removal of ECM using hyaluronidase induced an increase in surface expression of GluN2B. This was due to decreased endocytosis of surface GluNB-containing receptors. We further found a reduction in phosphorylation at Tyr1472, which negatively regulates their binding to the endocytotic AP2 complex. We propose that maturation of ECM could induce switch in NMDAR composition necessary for normal adult synaptic plasticity and that increased expression of GluN2B contributes to rejuvenation of plasticity after ECM removal in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-07003-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591221PMC
September 2017

Stress hormone rapidly tunes synaptic NMDA receptor through membrane dynamics and mineralocorticoid signalling.

Sci Rep 2017 08 14;7(1):8053. Epub 2017 Aug 14.

University de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000, Bordeaux, France.

Stress hormones, such as corticosteroids, modulate the transmission of hippocampal glutamatergic synapses and NMDA receptor (NMDAR)-dependent synaptic plasticity, favouring salient behavioural responses to the environment. The corticosterone-induced synaptic adaptations partly rely on changes in NMDAR signalling, although the cellular pathway underlying this effect remains elusive. Here, we demonstrate, using single molecule imaging and electrophysiological approaches in hippocampal neurons, that corticosterone specifically controls GluN2B-NMDAR surface dynamics and synaptic content through mineralocorticoid signalling. Strikingly, extracellular corticosterone was sufficient to increase the trapping of GluN2B-NMDAR within synapses. Functionally, corticosterone-induced potentiation of AMPA receptor content in synapses required the changes in NMDAR surface dynamics. These high-resolution imaging data unveiled that, in hippocampal networks, corticosterone is a natural, potent, fast and specific regulator of GluN2B-NMDAR membrane trafficking, tuning NMDAR-dependent synaptic adaptations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-08695-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556050PMC
August 2017

Cell- and Single Molecule-Based Methods to Detect Anti-N-Methyl-D-Aspartate Receptor Autoantibodies in Patients With First-Episode Psychosis From the OPTiMiSE Project.

Biol Psychiatry 2017 Nov 6;82(10):766-772. Epub 2017 Jul 6.

Interdisciplinary Institute for Neuroscience, UMR 5297, University of Bordeaux, France; Centre National de la Recherche Scientifique, France. Electronic address:

Circulating autoantibodies against glutamatergic N-methyl-D-aspartate receptor (NMDAR) have been reported in a proportion of patients with psychotic disorders, raising hopes for more appropriate treatment for these antibody-positive patients. However, the prevalence of circulating autoantibodies against glutamatergic NMDAR in psychotic disorders remains controversial, with detection prevalence rates and immunoglobulin classes varying considerably between studies, perhaps because of different detection methods. Here, we compared the results of serum assays for a large cohort of patients with first-episode psychosis using classical cell-based assays in three labs and a single molecule-based imaging method. Most assays and single molecule imaging in live hippocampal neurons revealed the presence of circulating autoantibodies against glutamatergic NMDAR in approximately 5% of patients with first-episode psychosis. However, some heterogeneity between cell-based assays was clearly observed, highlighting the urgent need for new sensitive methods to detect the presence of low-titer autoantibodies against glutamatergic NMDAR in seropositive patients who cannot be clinically identified from seronegative ones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2017.06.015DOI Listing
November 2017

Prehistoric enemies within: The contribution of human endogenous retroviruses to neurological diseases. Meeting report: "Second International Workshop on Human Endogenous Retroviruses and Disease", Washington DC, March 13th and 14th 2017.

Mult Scler Relat Disord 2017 Jul 1;15:18-23. Epub 2017 May 1.

Department of Neurology, Heinrich-Heine-University Düsseldorf, Germany. Electronic address:

The Second International Workshop on Human Endogenous Retroviruses and Disease, Washington DC, March 13-14 2017 brought together international basic and clinical scientists investigating the involvement of human endogenous retroviruses (HERVs) in complex human diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msard.2017.05.001DOI Listing
July 2017

Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses.

Elife 2017 06 9;6. Epub 2017 Jun 9.

Interdisciplinary Institute for NeuroSciences, CNRS UMR 5297, Bordeaux, France.

The subunit composition of synaptic NMDA receptors (NMDAR), such as the relative content of GluN2A- and GluN2B-containing receptors, greatly influences the glutamate synaptic transmission. Receptor co-agonists, glycine and D-serine, have intriguingly emerged as potential regulators of the receptor trafficking in addition to their requirement for its activation. Using a combination of single-molecule imaging, biochemistry and electrophysiology, we show that glycine and D-serine relative availability at rat hippocampal glutamatergic synapses regulate the trafficking and synaptic content of NMDAR subtypes. Acute manipulations of co-agonist levels, both ex vivo and in vitro, unveil that D-serine alter the membrane dynamics and content of GluN2B-NMDAR, but not GluN2A-NMDAR, at synapses through a process requiring PDZ binding scaffold partners. In addition, using FRET-based FLIM approach, we demonstrate that D-serine rapidly induces a conformational change of the GluN1 subunit intracellular C-terminus domain. Together our data fuels the view that the extracellular microenvironment regulates synaptic NMDAR signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.25492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466419PMC
June 2017

Clinical and autoimmune features of a patient with autism spectrum disorder seropositive for anti-NMDA-receptor autoantibody.

Dialogues Clin Neurosci 2017 03;19(1):65-70

University Paris Est Créteil, Psychiatry department, University Hospital Henri Mondor, Public Hospitals of Paris (AP-HP), University Hospital Department of Personalized Neurology and Psychiatry (DHU PePSY), France; Translational Psychiatry Laboratory, National Institute of Health and Medical Research (Inserm) U955, France; FondaMental Foundation, France.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by dysfunctions in social interactions resulting from a complex interplay between immunogenetic and environmental risk factors. Autoimmunity has been proposed as a major etiological component of ASD. Whether specific autoantibodies directed against brain targets are involved in ASD remains an open question. Here, we identified within a cohort an ASD patient with multiple circulating autoantibodies, including the well-characterized one against glutamate NMDA receptor (NMDAR-Ab). The patient exhibited alexithymia and previously suffered from two major depressive episodes without psychotic symptoms. Using a single molecule-based imaging approach, we demonstrate that neither NMDAR-Ab type G immunoglobulin purified from the ASD patient serum, nor that from a seropositive healthy subject, disorganize membrane NMDAR complexes at synapses. These findings suggest that the autistic patient NMDAR-Abs do not play a direct role in the etiology of ASD and that other autoantibodies directed against neuronal targets should be investigated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442365PMC
March 2017

[Implication of human endogenous retroviruses in schizophrenia and bipolar disorder].

Med Sci (Paris) 2017 Apr 12;33(4):404-409. Epub 2017 May 12.

Pôle psychiatrie des hôpitaux universitaires Henri Mondor, AP-HP, université Paris-Est, DHU PePSY, hôpital Albert Chenevier, 40, rue de Mesly, 94000 Créteil, France - Inserm U955, équipe 15, psychiatrie translationnelle, 94000 Créteil, France - Fondation FondaMental, 94000 Créteil, France.

Schizophrenia and bipolar disorder are neuropsychiatric disorders of unknown origin. It seems that these two disorders share some common etiopathogenic mechanisms including genetic, environmental and inflammatory ones. Reactivation of the human endogenous retrovirus type W (HERV-W) can be a shared element in the pathophysiology of schizophrenia and bipolar disorder, linked to immuno-genetic and environment risk factors. We will present studies that have highlighted the presence of HERV-W in schizophrenic and bipolar disorder patients. We will then describe a two-hit model which could explain the common pathophysiological mechanism of affective and non-affective psychosis. Identification of immuno-inflammatory mediated subgroup of schizophrenia and bipolar disorder associated to HERV-W reactivation might open the way for the development of diagnostic biomarker and more targeted treatments. These new tools pave the way towards personalized psychiatry for a better care of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1051/medsci/20173304010DOI Listing
April 2017

The Clinical Challenge of Autoimmune Psychosis: Learning from Anti-NMDA Receptor Autoantibodies.

Front Psychiatry 2017 19;8:54. Epub 2017 Apr 19.

DHU PePSY et Pôle de psychiatrie et d'addictologie des Hôpitaux Universitaires Henri Mondor, AP-HP, Université Paris Est Créteil (UPEC), Créteil, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyt.2017.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396186PMC
April 2017