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1.
Front Cell Neurosci ; 13: 362, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440143

RESUMO

Viral vectors are attractive tools to express genes in neurons. Transduction of neurons with a recombinant, replication-deficient Sindbis viral vector is a method of choice for studying the effects of short-term protein overexpression on neuronal function. However, to which extent Sindbis by itself may affect neurons is not fully understood. We assessed effects of neuronal transduction with a Sindbis viral vector on the transcriptome and proteome in organotypic hippocampal slice cultures, and analyzed the electrophysiological properties of individual CA1 neurons, at 24 h and 72 h after viral vector injection. Whereas Sindbis caused substantial gene expression alterations, changes at the protein level were less pronounced. Alterations in transcriptome and proteome were predominantly limited to proteins involved in mediating anti-viral innate immune responses. Sindbis transduction did not affect the intrinsic electrophysiological properties of individual neurons: the membrane potential and neuronal excitability were similar between transduced and non-transduced CA1 neurons up to 72 h after Sindbis injection. Synaptic currents also remained unchanged upon Sindbis transduction, unless slices were massively infected for 72 h. We conclude that Sindbis viral vectors at low transduction rates are suitable for studying short-term effects of a protein of interest on electrophysiological properties of neurons, but not for studies on the regulation of gene expression.

2.
Elife ; 62017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28762944

RESUMO

Excitatory synaptic transmission is mediated by AMPA-type glutamate receptors (AMPARs). In CA1 pyramidal neurons of the hippocampus two types of AMPARs predominate: those that contain subunits GluA1 and GluA2 (GluA1/2), and those that contain GluA2 and GluA3 (GluA2/3). Whereas subunits GluA1 and GluA2 have been extensively studied, the contribution of GluA3 to synapse physiology has remained unclear. Here we show in mice that GluA2/3s are in a low-conductance state under basal conditions, and although present at synapses they contribute little to synaptic currents. When intracellular cyclic AMP (cAMP) levels rise, GluA2/3 channels shift to a high-conductance state, leading to synaptic potentiation. This cAMP-driven synaptic potentiation requires the activation of both protein kinase A (PKA) and the GTPase Ras, and is induced upon the activation of ß-adrenergic receptors. Together, these experiments reveal a novel type of plasticity at CA1 hippocampal synapses that is expressed by the activation of GluA3-containing AMPARs.


Assuntos
Região CA1 Hipocampal/fisiologia , Plasticidade Neuronal/fisiologia , Receptores de AMPA/metabolismo , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Região CA1 Hipocampal/citologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Knockout , Técnicas de Patch-Clamp , Células Piramidais/citologia , Células Piramidais/fisiologia , Receptores de AMPA/genética , Receptores Adrenérgicos beta/genética , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais , Proteínas ras/genética , Proteínas ras/metabolismo
3.
Proc Natl Acad Sci U S A ; 113(42): E6526-E6534, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27708157

RESUMO

Amyloid-ß (Aß) is a prime suspect for causing cognitive deficits during the early phases of Alzheimer's disease (AD). Experiments in AD mouse models have shown that soluble oligomeric clusters of Aß degrade synapses and impair memory formation. We show that all Aß-driven effects measured in these mice depend on AMPA receptor (AMPAR) subunit GluA3. Hippocampal neurons that lack GluA3 were resistant against Aß-mediated synaptic depression and spine loss. In addition, Aß oligomers blocked long-term synaptic potentiation only in neurons that expressed GluA3. Furthermore, although Aß-overproducing mice showed significant memory impairment, memories in GluA3-deficient congenics remained unaffected. These experiments indicate that the presence of GluA3-containing AMPARs is critical for Aß-mediated synaptic and cognitive deficits.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Memória , Receptores de AMPA/metabolismo , Sinapses/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/mortalidade , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Análise de Variância , Animais , Comportamento Animal , Células CHO , Condicionamento Psicológico , Cricetulus , Espinhas Dendríticas , Medo/psicologia , Feminino , Hipocampo/citologia , Hipocampo/fisiologia , Potenciação de Longa Duração , Masculino , Potenciais da Membrana , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Células Piramidais/citologia , Células Piramidais/metabolismo , Receptores de AMPA/genética
4.
Neuropsychopharmacology ; 41(8): 2001-10, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26708106

RESUMO

Alterations in reward processes may underlie motivational and anhedonic symptoms in depression and schizophrenia. However it remains unclear whether these alterations are disorder-specific or shared, and whether they clearly relate to symptom generation or not. We studied brain responses to unexpected rewards during a simulated slot-machine game in 24 patients with depression, 21 patients with schizophrenia, and 21 healthy controls using functional magnetic resonance imaging. We investigated relationships between brain activation, task-related motivation, and questionnaire rated anhedonia. There was reduced activation in the orbitofrontal cortex, ventral striatum, inferior temporal gyrus, and occipital cortex in both depression and schizophrenia in comparison with healthy participants during receipt of unexpected reward. In the medial prefrontal cortex both patient groups showed reduced activation, with activation significantly more abnormal in schizophrenia than depression. Anterior cingulate and medial frontal cortical activation predicted task-related motivation, which in turn predicted anhedonia severity in schizophrenia. Our findings provide evidence for overlapping hypofunction in ventral striatal and orbitofrontal regions in depression and schizophrenia during unexpected reward receipt, and for a relationship between unexpected reward processing in the medial prefrontal cortex and the generation of motivational states.


Assuntos
Anedonia/fisiologia , Transtorno Depressivo/fisiopatologia , Lobo Frontal/fisiopatologia , Recompensa , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Estriado Ventral/fisiopatologia , Adulto , Mapeamento Encefálico , Feminino , Jogos Experimentais , Humanos , Imageamento por Ressonância Magnética , Masculino , Motivação , Vias Neurais/fisiopatologia
5.
Front Psychol ; 6: 1280, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26379600

RESUMO

In the research domain framework (RDoC), dysfunctional reward expectation has been proposed to be a cross-diagnostic domain in psychiatry, which may contribute to symptoms common to various neuropsychiatric conditions, such as anhedonia or apathy/avolition. We used a modified version of the Monetary Incentive Delay (MID) paradigm to obtain functional MRI images from 22 patients with schizophrenia, 24 with depression and 21 controls. Anhedonia and other symptoms of depression, and overall positive and negative symptomatology were also measured. We hypothesized that the two clinical groups would have a reduced activity in the ventral striatum when anticipating reward (compared to anticipation of a neutral outcome) and that striatal activation would correlate with clinical measures of motivational problems and anhedonia. Results were consistent with the first hypothesis: two clusters in both the left and right ventral striatum were found to differ between the groups in reward anticipation. Post-hoc analysis showed that this was due to higher activation in the controls compared to the schizophrenia and the depression groups in the right ventral striatum, with activation differences between depression and controls also seen in the left ventral striatum. No differences were found between the two patient groups, and there were no areas of abnormal cortical activation in either group that survived correction for multiple comparisons. Reduced ventral striatal activity was related to greater anhedonia and overall depressive symptoms in the schizophrenia group, but not in the participants with depression. Findings are discussed in relation to previous literature but overall are supporting evidence of reward system dysfunction across the neuropsychiatric continuum, even if the specific clinical relevance is still not fully understood. We also discuss how the RDoC approach may help to solve some of the replication problems in psychiatric fMRI research.

6.
PLoS One ; 7(2): e31503, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22348092

RESUMO

Neurexin-1 alpha (NRXN1α) belongs to the family of cell adhesion molecules (CAMs), which are involved in the formation of neuronal networks and synapses. NRXN1α gene mutations have been identified in neuropsychiatric diseases including Schizophrenia (SCZ) and Autism Spectrum Disorder (ASD). In order to get a better understanding of the pleiotropic behavioral manifestations caused by NRXN1α gene mutations, we performed a behavioral study of Nrxn1α heterozygous knock-out (+/-) mice and observed increased responsiveness to novelty and accelerated habituation to novel environments compared to wild type (+/+) litter-mates. However, this effect was mainly observed in male mice, strongly suggesting that gender-specific mechanisms play an important role in Nrxn1α-induced phenotypes.


Assuntos
Adaptação Fisiológica/genética , Moléculas de Adesão de Célula Nervosa/genética , Animais , Proteínas de Ligação ao Cálcio , Feminino , Genótipo , Masculino , Camundongos , Camundongos Knockout , Mutação , Moléculas de Adesão de Célula Nervosa/fisiologia , Fenótipo , Fatores Sexuais
7.
Behav Brain Res ; 209(2): 241-8, 2010 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-20138918

RESUMO

When anxiety-related behaviour in animals appears to lack adaptive value, it might be defined as pathological. Adaptive behaviour can be assessed for example by changes in behavioural responses over time, i.e. habituation. Thus, non-adaptive anxiety would be reflected by a lack of habituation. Recently, we found that 129P3/J mice are characterised by non-adaptive avoidance behaviour after repeated test exposure. The present study was aimed at investigating the sensitivity of the behavioural profile of these animals to exposure to a chronic mild stress (CMS) paradigm followed by repeated exposure to the modified hole board test. If the behavioural profile of 129P3/J mice mirrors pathological anxiety, their behavioural habituation under repeated test exposure conditions should be affected by CMS treatment. The results confirm the profound lack of habituation with respect to anxiety-related behaviour in both control and CMS treated mice. Additionally, CMS treated animals revealed a lower exploratory behaviour, reduced locomotor activity and increased arousal-related behaviour over time when compared to control individuals, proving an extension of their impaired habituation behaviour. Although no effects of CMS treatment on plasma corticosterone levels were found, higher immediate early gene expression in the bed nucleus of the stria terminalis and the ventrolateral periaqueductal grey in CMS treated mice indicated that 129P3/J mice are susceptible to the negative effects of CMS treatment at both the behavioural and the functional level. These results support the hypothesis that 129P3/J mice might be an interesting model for pathological anxiety.


Assuntos
Ansiedade/fisiopatologia , Habituação Psicofisiológica/fisiologia , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia , Análise de Variância , Animais , Ansiedade/metabolismo , Aprendizagem da Esquiva/fisiologia , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Contagem de Células , Corticosterona/sangue , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Abrigo para Animais , Masculino , Camundongos , Atividade Motora/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Meio Social , Estresse Psicológico/metabolismo
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