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1.
Transl Psychiatry ; 11(1): 444, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34462417

RESUMO

A dysfunction of the glutamatergic transmission, especially of the NMDA receptor (NMDAR), constitutes one of the main biological substrate of psychotic disorders, such as schizophrenia. The NMDAR signaling hypofunction, through genetic and/or environmental insults, would cause a neurodevelopmental myriad of molecular, cellular, and network alterations that persist throughout life. Yet, the mechanisms underpinning NMDAR dysfunctions remain elusive. Here, we compared the membrane trafficking of NMDAR in three gold-standard models of schizophrenia, i.e., patient's cerebrospinal fluids, genetic manipulations of susceptibility genes, and prenatal developmental alterations. Using a combination of single nanoparticle tracking, electrophysiological, biochemical, and behavioral approaches in rodents, we identified that the NMDAR trafficking in hippocampal neurons was consistently altered in all these different models. Artificial manipulations of the NMDAR surface dynamics with competing ligands or antibody-induced receptor cross-link in the developing rat brain were sufficient to regulate the adult acoustic startle reflex and compensate for an early pathological challenge. Collectively, we show that the NMDAR trafficking is markedly altered in all clinically relevant models of psychosis, opening new avenues of therapeutical strategies.


Assuntos
Transtornos Psicóticos , Esquizofrenia , Animais , Hipocampo/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais
2.
Biol Psychiatry ; 90(1): 9-15, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33536130

RESUMO

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.


Assuntos
Antipsicóticos , Transtornos Psicóticos , Esquizofrenia , Antipsicóticos/uso terapêutico , Europa (Continente) , Humanos , Transtornos Psicóticos/tratamento farmacológico , Receptores de N-Metil-D-Aspartato , Esquizofrenia/tratamento farmacológico
3.
Science ; 363(6425): 413-417, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30679375

RESUMO

How neuronal connections are established and organized into functional networks determines brain function. In the mammalian cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made toward parsing interneuron diversity, yet the molecular mechanisms by which interneuron-specific connectivity motifs emerge remain unclear. In this study, we investigated transcriptional dynamics in different classes of interneurons during the formation of cortical inhibitory circuits in mouse. We found that whether interneurons form synapses on the dendrites, soma, or axon initial segment of pyramidal cells is determined by synaptic molecules that are expressed in a subtype-specific manner. Thus, cell-specific molecular programs that unfold during early postnatal development underlie the connectivity patterns of cortical interneurons.


Assuntos
Córtex Cerebral/fisiologia , Interneurônios/fisiologia , Sinapses/genética , Sinapses/fisiologia , Animais , Dendritos/genética , Dendritos/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Células Piramidais/fisiologia , Análise de Sequência de RNA , Transcrição Gênica , Transcriptoma
4.
J Neurosci Methods ; 304: 76-82, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29684464

RESUMO

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.


Assuntos
Autoanticorpos/análise , Autoanticorpos/metabolismo , Nanopartículas/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/imunologia , Imagem Individual de Molécula/métodos , Animais , Células Cultivadas , Embrião de Mamíferos , Hipocampo/citologia , Humanos , Ratos
6.
Nat Commun ; 8(1): 1791, 2017 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-29176681

RESUMO

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.


Assuntos
Autoanticorpos/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Esquizofrenia/imunologia , Sinapses/metabolismo , Adulto , Animais , Autoanticorpos/sangue , Autoanticorpos/metabolismo , Cálcio/metabolismo , Efrina-B2/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Células HEK293 , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Potenciação de Longa Duração/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Neurônios , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/sangue , Imagem Individual de Molécula , Sinapses/imunologia , Transmissão Sináptica/imunologia , Adulto Jovem
7.
Biol Psychiatry ; 82(10): 766-772, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28780967

RESUMO

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.


Assuntos
Autoanticorpos/análise , Autoanticorpos/imunologia , Fluorimunoensaio/métodos , Neurônios/citologia , Neurônios/imunologia , Transtornos Psicóticos/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Imagem Individual de Molécula/métodos , Adulto , Células Cultivadas , Feminino , Hipocampo/citologia , Humanos , Masculino , Adulto Jovem
8.
Cell Death Dis ; 7(11): e2466, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27831563

RESUMO

N-methyl-d-aspartate receptors (NMDARs) are ion channels whose synaptic versus extrasynaptic localization critically influences their functions. This distribution of NMDARs is highly dependent on their lateral diffusion at the cell membrane. Each obligatory subunit of NMDARs (GluN1 and GluN2) contains two extracellular clamshell-like domains with an agonist-binding domain and a distal N-terminal domain (NTD). To date, the roles and dynamics of the NTD of the GluN1 subunit in NMDAR allosteric signaling remain poorly understood. Using single nanoparticle tracking in mouse neurons, we demonstrate that the extracellular neuronal protease tissue-type plasminogen activator (tPA), well known to have a role in the synaptic plasticity and neuronal survival, leads to a selective increase of the surface dynamics and subsequent diffusion of extrasynaptic NMDARs. This process explains the previously reported ability of tPA to promote NMDAR-mediated calcium influx. In parallel, we developed a monoclonal antibody capable of specifically blocking the interaction of tPA with the NTD of the GluN1 subunit of NMDAR. Using this original approach, we demonstrate that the tPA binds the NTD of the GluN1 subunit at a lysine in position 178. Accordingly, when applied to mouse neurons, our selected antibody (named Glunomab) leads to a selective reduction of the tPA-mediated surface dynamics of extrasynaptic NMDARs, subsequent signaling and neurotoxicity, both in vitro and in vivo. Altogether, we demonstrate that the tPA is a ligand of the NTD of the obligatory GluN1 subunit of NMDAR acting as a modulator of their dynamic distribution at the neuronal surface and subsequent signaling.


Assuntos
Membrana Celular/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Ativador de Plasminogênio Tecidual/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Difusão , Fibrinolisina/farmacologia , Células HEK293 , Humanos , Lisina/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Neurônios/efeitos dos fármacos , Neurotoxinas/toxicidade , Domínios Proteicos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/química , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos
9.
Proc Natl Acad Sci U S A ; 111(39): 14265-70, 2014 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-25225407

RESUMO

The rodent adrenal hormone corticosterone (CORT) reaches the brain in hourly ultradian pulses, with a steep rise in amplitude before awakening. The impact of a single CORT pulse on glutamatergic transmission is well documented, but it remains poorly understood how consecutive pulses impact on glutamate receptor trafficking and synaptic plasticity. By using high-resolution imaging and electrophysiological approaches, we report that a single pulse of CORT to hippocampal networks causes synaptic enrichment of glutamate receptors and increased responses to spontaneously released glutamatergic vesicles, collectively abrogating the ability to subsequently induce synaptic long-term potentiation. Strikingly, a second pulse of CORT one hour after the first--mimicking ultradian pulses--completely normalizes all aspects of glutamate transmission investigated, restoring the plastic range of the synapse. The effect of the second pulse is precisely timed and depends on a nongenomic glucocorticoid receptor-dependent pathway. This normalizing effect through a sequence of CORT pulses--as seen around awakening--may ensure that hippocampal glutamatergic synapses remain fully responsive and able to encode new stress-related information when daily activities start.


Assuntos
Corticosterona/administração & dosagem , Corticosterona/fisiologia , Ácido Glutâmico/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Ciclos de Atividade/fisiologia , Animais , Células Cultivadas , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/fisiologia , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/fisiologia
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