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1.
Nat Commun ; 14(1): 8312, 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-38097535

RESUMO

The consolidation of recent memories depends on memory replays, also called ripples, generated within the hippocampus during slow-wave sleep, and whose inactivation leads to memory impairment. For now, the mobilisation, localisation and importance of synaptic plasticity events associated to ripples are largely unknown. To tackle this question, we used cell surface AMPAR immobilisation to block post-synaptic LTP within the hippocampal region of male mice during a spatial memory task, and show that: 1- hippocampal synaptic plasticity is engaged during consolidation, but is dispensable during encoding or retrieval. 2- Plasticity blockade during sleep results in apparent forgetting of the encoded rule. 3- In vivo ripple recordings show a strong effect of AMPAR immobilisation when a rule has been recently encoded. 4- In situ investigation suggests that plasticity at CA3-CA3 recurrent synapses supports ripple generation. We thus propose that post-synaptic AMPAR mobility at CA3 recurrent synapses is necessary for ripple-dependent rule consolidation.


Assuntos
Consolidação da Memória , Camundongos , Masculino , Animais , Consolidação da Memória/fisiologia , Hipocampo/fisiologia , Plasticidade Neuronal/fisiologia , Sono/fisiologia , Memória Espacial , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/fisiologia
3.
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
4.
J Neurosci ; 37(46): 11114-11126, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29030432

RESUMO

Classical and systems genetics have identified wide networks of genes associated with cognitive and neurodevelopmental diseases. In parallel to deciphering the role of each of these genes in neuronal or synaptic function, evaluating the response of neuronal and molecular networks to gene loss of function could reveal some pathophysiological mechanisms potentially accessible to nongenetic therapies. Loss of function of the Rho-GAP oligophrenin-1 is associated with cognitive impairments in both human and mouse. Upregulation of both PKA and ROCK has been reported in Ophn1-/y mice, but it remains unclear whether kinase hyperactivity contributes to the behavioral phenotypes. In this study, we thoroughly characterized a prominent perseveration phenotype displayed by Ophn1-deficient mice using a Y-maze spatial working memory (SWM) test. We report that Ophn1 deficiency in the mouse generated severe cognitive impairments, characterized by both a high occurrence of perseverative behaviors and a lack of deliberation during the SWM test. In vivo and in vitro pharmacological experiments suggest that PKA dysregulation in the mPFC underlies cognitive dysfunction in Ophn1-deficient mice, as assessed using a delayed spatial alternation task results. Functionally, mPFC neuronal networks appeared to be affected in a PKA-dependent manner, whereas hippocampal-PFC projections involved in SWM were not affected in Ophn1-/y mice. Thus, we propose that discrete gene mutations in intellectual disability might generate "secondary" pathophysiological mechanisms, which are prone to become pharmacological targets for curative strategies in adult patients.SIGNIFICANCE STATEMENT Here we report that Ophn1 deficiency generates severe impairments in performance at spatial working memory tests, characterized by a high occurrence of perseverative behaviors and a lack of decision making. This cognitive deficit is consecutive to PKA deregulation in the mPFC that prevents Ophn1 KO mice to exploit a correctly acquired rule. Functionally, mPFC neuronal networks appear to be affected in a PKA-dependent manner, whereas behaviorally important hippocampal projections were preserved by the mutation. Thus, we propose that discrete gene mutations in intellectual disability can generate "secondary" pathophysiological mechanisms prone to become pharmacological targets for curative strategies in adults.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas do Citoesqueleto/deficiência , Proteínas Ativadoras de GTPase/deficiência , Transtornos da Memória/metabolismo , Memória de Curto Prazo/fisiologia , Proteínas Nucleares/deficiência , Córtex Pré-Frontal/metabolismo , Animais , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Rede Nervosa/metabolismo , Rede Nervosa/fisiopatologia , Técnicas de Cultura de Órgãos , Córtex Pré-Frontal/fisiopatologia , Distribuição Aleatória
5.
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
6.
J Neuroinflammation ; 12: 202, 2015 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-26538404

RESUMO

BACKGROUND: Microglia cells are the resident macrophages of the central nervous system and are considered its first line of defense. In the normal brain, their ramified processes are highly motile, constantly scanning the surrounding brain tissue and rapidly moving towards sites of acute injury or danger signals. These microglial dynamics are thought to be critical for brain homeostasis. Under pathological conditions, microglial cells undergo "activation," which modifies many of their molecular and morphological properties. Investigations of the effects of activation on motility are limited and have given mixed results. In particular, little is known about how microglial motility is altered in epilepsy, which is characterized by a strong inflammatory reaction and microglial activation. METHODS: We used a mouse model of status epilepticus induced by kainate injections and time-lapse two-photon microscopy to image GFP-labeled microglia in acute hippocampal brain slices. We studied how microglial activation affected the motility of microglial processes, including basal motility, and their responses to local triggering stimuli. RESULTS: Our study reveals that microglial motility was largely preserved in kainate-treated animals, despite clear signs of microglial activation. In addition, whereas the velocities of microglial processes during basal scanning and towards a laser lesion were unaltered 48 h after status epilepticus, we observed an increase in the size of the territory scanned by single microglial processes during basal motility and an elevated directional velocity towards a pipette containing a purinergic agonist. CONCLUSIONS: Microglial activation differentially impacted the dynamic scanning behavior of microglia in response to specific acute noxious stimuli, which may be an important feature of the adaptive behavior of microglia during pathophysiological conditions.


Assuntos
Microglia/patologia , Estado Epiléptico/patologia , Animais , Receptor 1 de Quimiocina CX3C , Movimento Celular , Agonistas de Aminoácidos Excitatórios , Hipocampo/patologia , Técnicas In Vitro , Inflamação/patologia , Ácido Caínico , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Agonistas do Receptor Purinérgico P2Y/farmacologia , Receptores de Quimiocinas/genética , Receptores Purinérgicos P2Y12 , Estado Epiléptico/induzido quimicamente
7.
Brain Struct Funct ; 220(6): 3673-82, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25158900

RESUMO

The process of learning mainly depends on the ability to store new information, while the ability to retrieve this information and express appropriate behaviors are also crucial for the adaptation of individuals to environmental cues. Thereby, all three components contribute to the cognitive fitness of an individual. While a lack of behavioral adaptation is a recurrent trait of intellectually disabled patients, discriminating between memory formation, memory retrieval or behavioral expression deficits is not easy to establish. Here, we report some deficits in contextual fear behavior in knockout mice for the intellectual disability gene Il1rapl1. Functional in vivo experiments revealed that the lack of conditioned response resulted from a local inhibitory to excitatory (I/E) imbalance in basolateral amygdala (BLA) consecutive to a loss of excitatory drive onto BLA principal cells by caudal hippocampus axonal projections. A normalization of the fear behavior was obtained in adult mutant mice following opsin-based in vivo synaptic priming of hippocampo-BLA synapses in adult il1rapl1 knockout mice, indicating that synaptic efficacy at hippocampo-BLA projections is crucial for contextual fear memory expression. Importantly, because this restoration was obtained after the learning phase, our results suggest that some of the genetically encoded cognitive deficits in humans may originate from a lack of restitution of genuinely formed memories rather than an exclusive inability to store new memories.


Assuntos
Tonsila do Cerebelo/fisiologia , Medo/fisiologia , Hipocampo/fisiologia , Deficiência Intelectual/fisiopatologia , Proteína Acessória do Receptor de Interleucina-1/fisiologia , Animais , Condicionamento Clássico/fisiologia , Modelos Animais de Doenças , Deficiência Intelectual/genética , Proteína Acessória do Receptor de Interleucina-1/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sinapses/fisiologia , Potenciais Sinápticos
8.
Philos Trans R Soc Lond B Biol Sci ; 369(1633): 20130160, 2014 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-24298161

RESUMO

Loss-of-function mutations in the gene encoding for the RhoGAP protein of oligophrenin-1 (OPHN1) lead to cognitive disabilities (CDs) in humans, yet the underlying mechanisms are not known. Here, we show that in mice constitutive lack of Ophn1 is associated with dysregulation of the cyclic adenosine monophosphate/phosphate kinase A (cAMP/PKA) signalling pathway in a brain-area-specific manner. Consistent with a key role of cAMP/PKA signalling in regulating presynaptic function and plasticity, we found that PKA-dependent presynaptic plasticity was completely abolished in affected brain regions, including hippocampus and amygdala. At the behavioural level, lack of OPHN1 resulted in hippocampus- and amygdala-related learning disabilities which could be fully rescued by the ROCK/PKA kinase inhibitor fasudil. Together, our data identify OPHN1 as a key regulator of presynaptic function and suggest that, in addition to reported postsynaptic deficits, loss of presynaptic plasticity contributes to the pathophysiology of CDs.


Assuntos
Proteínas do Citoesqueleto/deficiência , Proteínas Ativadoras de GTPase/deficiência , Deficiências da Aprendizagem/genética , Plasticidade Neuronal/fisiologia , Proteínas Nucleares/deficiência , Terminações Pré-Sinápticas/fisiologia , Transdução de Sinais/fisiologia , Animais , Western Blotting , Condicionamento Psicológico , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas do Citoesqueleto/genética , Estimulação Elétrica , Proteínas Ativadoras de GTPase/genética , Deficiências da Aprendizagem/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética
9.
J Neurosci ; 33(34): 13805-19, 2013 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-23966701

RESUMO

Intellectual disorders (IDs) have been regularly associated with morphological and functional deficits at glutamatergic synapses in both humans and rodents. How these synaptic deficits may lead to the variety of learning and memory deficits defining ID is still unknown. Here we studied the functional and behavioral consequences of the ID gene il1rapl1 deficiency in mice and reported that il1rapl1 constitutive deletion alters cued fear memory formation. Combined in vivo and in vitro approaches allowed us to unveil a causal relationship between a marked inhibitory/excitatory (I/E) imbalance in dedicated amygdala neuronal subcircuits and behavioral deficits. Cell-targeted recordings further demonstrated a morpho-functional impact of the mutation at thalamic projections contacting principal cells, whereas the same afferents on interneurons are unaffected by the lack of Il1rapl1. We thus propose that excitatory synapses have a heterogeneous vulnerability to il1rapl1 gene constitutive mutation and that alteration of a subset of excitatory synapses in neuronal circuits is sufficient to generate permanent cognitive deficits.


Assuntos
Potenciais Pós-Sinápticos Excitadores/genética , Deficiência Intelectual/complicações , Transtornos da Memória/etiologia , Tonsila do Cerebelo/citologia , Anestésicos Locais/farmacologia , Animais , Aprendizagem por Associação/fisiologia , Córtex Cerebral/citologia , Channelrhodopsins , Condicionamento Psicológico/fisiologia , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/ultraestrutura , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Medo/fisiologia , Antagonistas GABAérgicos/farmacologia , Glutamato Descarboxilase/genética , Proteínas de Fluorescência Verde/genética , Técnicas In Vitro , Deficiência Intelectual/genética , Proteína Acessória do Receptor de Interleucina-1/genética , Proteína Acessória do Receptor de Interleucina-1/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Inibição Neural/efeitos dos fármacos , Inibição Neural/genética , Neurônios/fisiologia , Neurônios/ultraestrutura
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