RESUMO
We used a virtual navigation paradigm in a city environment to assess neuroanatomical correlates of cognitive deficits in schizophrenia spectrum disorders (SSD). We studied a total of N = 36 subjects: 18 with SSD and 18 matched unaffected controls. Participants completed 10 rapid, single-trial navigation tasks within the virtual city while undergoing functional magnetic resonance imaging (fMRI). All trials tested ability to find different targets seen earlier, during the passive viewing of a path around different city blocks. SSD patients had difficulty finding previously-encountered targets, were less likely to find novel shortcuts to targets, and more likely to attempt retracing of the path observed during passive viewing. Based on a priori region-of-interest analyses, SSD participants had hyperactivation of the left hippocampus when passively viewing turns, hyperactivation of the left caudate when finding targets, and hypoactivation of a focal area of the dorsolateral prefrontal cortex when targets were initially shown during passive viewing. We propose that these brain-behaviour relations may bias or reinforce stimulus-response navigation approaches in SSD and underlie impaired performance when allocentric spatial memory is required, such as when forming efficient shortcuts. This pattern may extend to more general cognitive impairments in SSD that could be used to design remediation strategies.
Assuntos
Núcleo Caudado , Hipocampo , Imageamento por Ressonância Magnética , Esquizofrenia , Navegação Espacial , Humanos , Hipocampo/diagnóstico por imagem , Hipocampo/fisiopatologia , Masculino , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/fisiopatologia , Adulto , Núcleo Caudado/diagnóstico por imagem , Núcleo Caudado/fisiopatologia , Feminino , Navegação Espacial/fisiologia , Pessoa de Meia-Idade , Realidade VirtualRESUMO
Maternal immune activation (MIA) is a risk factor for multiple neurodevelopmental disorders; however, animal models developed to explore MIA mechanisms are sensitive to experimental factors, which has led to complexity in previous reports of the MIA phenotype. We sought to characterize an MIA protocol throughout development to understand how prenatal immune insult alters the trajectory of important neurodevelopmental processes, including the microglial regulation of synaptic spines and complement signaling. We used polyinosinic:polycytidylic acid (polyI:C) to induce MIA on gestational day 9.5 in CD-1 mice, and measured their synaptic spine density, microglial synaptic pruning, and complement protein expression. We found reduced dendritic spine density in the somatosensory cortex starting at 3-weeks-of-age with requisite increases in microglial synaptic pruning and phagocytosis, suggesting spine density loss was caused by increased microglial synaptic pruning. Additionally, we showed dysregulation in complement protein expression persisting into adulthood. Our findings highlight disruptions in the prenatal environment leading to alterations in multiple dynamic processes through to postnatal development. This could potentially suggest developmental time points during which synaptic processes could be measured as risk factors or targeted with therapeutics for neurodevelopmental disorders.
Assuntos
Proteínas do Sistema Complemento , Espinhas Dendríticas , Microglia , Poli I-C , Animais , Microglia/metabolismo , Microglia/efeitos dos fármacos , Microglia/imunologia , Camundongos , Feminino , Gravidez , Espinhas Dendríticas/metabolismo , Poli I-C/farmacologia , Proteínas do Sistema Complemento/metabolismo , Proteínas do Sistema Complemento/imunologia , Efeitos Tardios da Exposição Pré-Natal , Fagocitose , Modelos Animais de Doenças , Córtex Somatossensorial/efeitos dos fármacos , Córtex Somatossensorial/metabolismo , Sinapses/metabolismo , Sinapses/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacosRESUMO
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. There is no specific treatment for FXS due to the lack of therapeutic targets. We report here that Elongation Factor 1α (EF1α) forms a complex with two other proteins: Tripartite motif-containing protein 3 (TRIM3) and Murine double minute (Mdm2). Both EF1α-Mdm2 and EF1α-TRIM3 protein complexes are increased in the brain of Fmr1 knockout mice as a result of FMRP deficiency, which releases the normal translational suppression of EF1α mRNA and increases EF1α protein levels. Increased EF1α-Mdm2 complex decreases PSD-95 ubiquitination (Ub-PSD-95) and Ub-PSD-95-C1q interaction. The elevated level of TRIM3-EF1α complex is associated with decreased TRIM3-Complement Component 3 (C3) complex that inhibits the activation of C3. Both protein complexes thereby contribute to a reduction in microglia-mediated phagocytosis and dendritic spine pruning. Finally, we created a peptide that disrupts both protein complexes and restores dendritic spine plasticity and behavioural deficits in Fmr1 knockout mice. The EF1α-Mdm2 and EF1α-TRIM3 complexes could thus be new therapeutic targets for FXS.
Assuntos
Espinhas Dendríticas , Proteína do X Frágil da Deficiência Intelectual , Camundongos Knockout , Microglia , Plasticidade Neuronal , Fator 1 de Elongação de Peptídeos , Fagocitose , Animais , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Microglia/metabolismo , Camundongos , Plasticidade Neuronal/fisiologia , Espinhas Dendríticas/metabolismo , Fagocitose/fisiologia , Fator 1 de Elongação de Peptídeos/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/genética , Camundongos Endogâmicos C57BL , Masculino , Encéfalo/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Ubiquitinação , Complemento C3/metabolismoRESUMO
While most research and treatments for multiple sclerosis (MS) focus on autoimmune reactions causing demyelination, it is possible that neurodegeneration precedes the autoimmune response. Hence, glutamate receptor antagonists preventing excitotoxicity showed promise in MS animal models, though blocking glutamate signaling prevents critical neuronal functions. This study reports the discovery of a small molecule that prevents AMPA-mediated excitotoxicity by targeting an allosteric binding site. A machine learning approach was used to screen for small molecules targeting the AMPA receptor GluA2 subunit. The lead candidate has potent effects in restoring neurological function and myelination while reducing the immune response in experimental autoimmune encephalitis and cuprizone MS mouse models without affecting basal neurotransmission or learning and memory. These findings facilitate development of a treatment for MS with a different mechanism of action than current immune modulatory drugs and avoids important off-target effects of glutamate receptor antagonists. This class of MS therapeutics could be useful as an alternative or complementary treatment to existing therapies.
Assuntos
Esclerose Múltipla , Camundongos , Animais , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de AMPA , Neurônios/metabolismoRESUMO
Serum amyloid P component (SAP) is a universal constituent of human amyloid deposits including those in Alzheimer's disease. SAP has been observed to be elevated in patients with depression, and higher SAP levels are associated with better response to the antidepressant escitalopram. The mechanisms underlying these clinical observations remain unclear. We examined the effect of SAP on serotonin transporter (SERT) expression and localization using Western blot, confocal microscopy, and positron emission tomography with the radioligand [11C]DASB. We also investigated the effect of SAP on treatment response to escitalopram in mice with the forced swim test (FST), a classical behaviour paradigm to assess antidepressant effects. SAP reduced [11C]DASB binding as an index of SERT levels, consistent with Western blots showing decreased total SAP protein because of increased protein degradation. In conjunction with the global decrease in SERT levels, SAP also promotes VAMP-2 mediated SERT membrane insertion. SAP levels are correlated with behavioural despair and SSRI treatment response in mice with FST. In MDD patients, the SAP and membrane SERT levels are correlated with response to SSRI treatment. SAP has complex effects on SERT levels and localization, thereby modulating the effect of SSRIs, which could partially explain clinical variability in antidepressant treatment response. These results add to our understanding of the mechanism for antidepressant drug action, and with further work could be of clinical utility.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Serotonina , Componente Amiloide P Sérico , Humanos , Camundongos , Animais , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Componente Amiloide P Sérico/metabolismo , Escitalopram , Antidepressivos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
The glucocorticoid receptor (GR) forms a protein complex with FKBP51 that is increased in post-traumatic stress disorder (PTSD) and by fear conditioned learning. Disrupting the GR-FKBP51 complex with a synthetic peptide can block the storage or retrieval of fear conditioned memories, which could be a novel approach to the alleviate fear associated memory in PTSD. However, a potential unacceptable side effect could be the impairment of other types of memory. Thus, we investigated the effect of disrupting the GR-FKBP51 complex on recognition memory using the novel object and displaced object recognition tasks, spatial memory in the Morris water maze, and on social interaction in Crawley's three-chamber social interaction test. We did not observe adverse effects on these other types of memory and conclude that the GR-FKBP51 interaction remains a promising target for treating psychiatric disorders characterized by unwanted aversive memories such as in PTSD.
Assuntos
Receptores de Glucocorticoides , Reconhecimento Psicológico , Transtornos de Estresse Pós-Traumáticos , Proteínas de Ligação a Tacrolimo , Medo , Humanos , Receptores de Glucocorticoides/metabolismo , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismoRESUMO
BACKGROUND: For decades, the dopamine D2 receptor (D2R) has been known as the main target of antipsychotic medications, but the mechanism for antipsychotic effects beyond this pharmacological target remains unclear. Disrupted-in-schizophrenia 1 (DISC1) is a gene implicated in the etiology of schizophrenia, and we have found elevated levels of the D2R-DISC1 complex in the postmortem brain tissue of patients with schizophrenia. METHODS: We used coimmunoprecipitation to measure D2R-DISC1 complex levels in peripheral blood samples from patients with schizophrenia and unaffected controls in 3 cohorts (including males and females) from different hospitals. We also used label-free mass spectrometry to conduct proteomic analysis of these samples. RESULTS: Levels of the D2R-DISC1 complex were elevated in the peripheral blood samples of patients with schizophrenia from 3 independent cohorts, and were normalized with antipsychotic treatment. Proteomic analysis of the blood samples from patients with high D2R-DISC1 complex levels that were normalized with antipsychotic treatment revealed a number of altered proteins and pathways associated with D2R, DISC1 and the D2R-DISC1 complex. We identified additional proteins and pathways that were associated with antipsychotic treatment in schizophrenia, and that may also be novel targets for schizophrenia treatment. LIMITATIONS: Sample sizes were relatively small, but were sufficient to detect associations between D2R-DISC1 levels, schizophrenia and treatment response. The relevance of leukocyte changes to the symptoms of schizophrenia is unknown. The coimmunoprecipitation lanes included several nonspecific bands. CONCLUSION: Levels of the D2R-DISC1 complex were elevated in patients with schizophrenia and reduced with antipsychotic treatment. This finding reinforces the independent role of each protein in schizophrenia. Our results enhanced our understanding of the molecular pathways involved in schizophrenia and in antipsychotic medications, and identified novel potential molecular targets for treating schizophrenia.
Assuntos
Antipsicóticos , Proteínas do Tecido Nervoso , Receptores de Dopamina D2 , Esquizofrenia , Antipsicóticos/uso terapêutico , Feminino , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Proteômica , Receptores de Dopamina D2/genética , Esquizofrenia/genéticaRESUMO
Epigenetic gene-regulation abnormalities have been implicated in various neuropsychiatric disorders including schizophrenia and depression, as well as in the regulation of mood and anxiety. In addition, epigenetic mechanisms are involved in the actions of psychiatric drugs. Current anxiolytic drugs have significant shortcomings, and development of new medications is warranted. Two proteins, G9a (also known as EHMT2 or KMT1C) and GLP (G9a-like protein, also known as EHMT1 or KMT1D), which methylate lysine 9 of histone H3 (H3K9), could be promising anxiolytic targets. Postnatal genetic knock-out of G9a reduces anxiety-related behavior, consistent with the reduction of G9a levels by some medications used to treat anxiety (amitriptyline, imipramine and paroxetine). Conversely, there is increased anxiety-like behavior in mice with GLP haplodeficiency. We sought to determine whether two pharmacological inhibitors of G9a/GLP, UNC0642 and A-366, would have similar effects to genetic G9a/GLP insufficiency. We found that G9a/GLP inhibition with either compound reduced anxiety-like behaviors when administered to adult mice, in conjunction with decreased H3K9 methylation in the brain. In contrast, exposure to these compounds from embryonic day 9.5 (E9.5) until birth increased anxiety-like behaviors and decreased social interaction in adulthood, while H3K9 methylation was at normal levels in the brains of the adult mice. These findings reinforce genetic evidence that G9a/GLP has different effects on anxiety-like behavior at different stages of brain development, and suggest that targeting this histone methyltransferase pathway could be useful for developing new anxiolytic drugs. These data also suggest that antidepressant exposure in utero could have negative effects in adulthood, and further investigation of these effects is warranted.
Assuntos
Ansiolíticos/uso terapêutico , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Indóis/uso terapêutico , Quinazolinas/uso terapêutico , Compostos de Espiro/uso terapêutico , Animais , Diazepam/uso terapêutico , Relação Dose-Resposta a Droga , Epigênese Genética , Feminino , Histonas/genética , Histonas/metabolismo , Masculino , Metilação , Camundongos Endogâmicos C57BL , Processamento de Proteína Pós-Traducional , Cloridrato de Venlafaxina/uso terapêuticoRESUMO
Depression and substance use disorders are often comorbid, but the reasons for this are unclear. In human studies, it is difficult to determine how one disorder may affect predisposition to the other and what the underlying mechanisms might be. Instead, animal studies allow experimental induction of behaviors relevant to depression and drug-taking, and permit direct interrogation of changes to neural circuits and molecular pathways. While this field is still new, here we review animal studies that investigate whether depression-like states increase vulnerability to drug-taking behaviors. Since chronic psychosocial stress can precipitate or predispose to depression in humans, we review studies that use psychosocial stressors to produce depression-like phenotypes in animals. Specifically, we describe how postweaning isolation stress, repeated social defeat stress, and chronic mild (or unpredictable) stress affect behaviors relevant to substance abuse, especially operant self-administration. Potential brain changes mediating these effects are also discussed where available, with an emphasis on mesocorticolimbic dopamine circuits. Postweaning isolation stress and repeated social defeat generally increase acquisition or maintenance of drug self-administration, and alter dopamine sensitivity in various brain regions. However, the effects of chronic mild stress on drug-taking have been much less studied. Future studies should consider standardizing stress-induction protocols, including female subjects, and using multi-hit models (e.g. genetic vulnerabilities and environmental stress).
Assuntos
Depressão/complicações , Modelos Animais de Doenças , Transtornos Relacionados ao Uso de Substâncias/complicações , Animais , Comportamento Animal , Encéfalo/metabolismo , Depressão/epidemiologia , Depressão/fisiopatologia , Diagnóstico Duplo (Psiquiatria) , Dopamina/metabolismo , Humanos , Autoadministração , Estresse Psicológico/complicações , Estresse Psicológico/psicologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologiaRESUMO
Patients with schizophrenia are at an increased risk for the development of depression. Overlap in the symptoms and genetic risk factors between the two disorders suggests a common etiological mechanism may underlie the presentation of comorbid depression in schizophrenia. Understanding these shared mechanisms will be important in informing the development of new treatments. Rodent models are powerful tools for understanding gene function as it relates to behavior. Examining rodent models relevant to both schizophrenia and depression reveals a number of common mechanisms. Current models which demonstrate endophenotypes of both schizophrenia and depression are reviewed here, including models of CUB and SUSHI multiple domains 1, PDZ and LIM domain 5, glutamate Delta 1 receptor, diabetic db/db mice, neuropeptide Y, disrupted in schizophrenia 1, and its interacting partners, reelin, maternal immune activation, and social isolation. Neurotransmission, brain connectivity, the immune system, the environment, and metabolism emerge as potential common mechanisms linking these models and potentially explaining comorbid depression in schizophrenia.