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1.
Proc Natl Acad Sci U S A ; 119(51): e2203711119, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36512497

RESUMO

The selenium-binding protein 1 (SELENBP1) has been reported to be up-regulated in the prefrontal cortex (PFC) of schizophrenia patients in postmortem reports. However, no causative link between SELENBP1 and schizophrenia has yet been established. Here, we provide evidence linking the upregulation of SELENBP1 in the PFC of mice with the negative symptoms of schizophrenia. We verified the levels of SELENBP1 transcripts in postmortem PFC brain tissues from patients with schizophrenia and matched healthy controls. We also generated transgenic mice expressing human SELENBP1 (hSELENBP1 Tg) and examined their neuropathological features, intrinsic firing properties of PFC 2/3-layer pyramidal neurons, and frontal cortex (FC) electroencephalographic (EEG) responses to auditory stimuli. Schizophrenia-like behaviors in hSELENBP1 Tg mice and mice expressing Selenbp1 in the FC were assessed. SELENBP1 transcript levels were higher in the brains of patients with schizophrenia than in those of matched healthy controls. The hSELENBP1 Tg mice displayed negative endophenotype behaviors, including heterotopias- and ectopias-like anatomical deformities in upper-layer cortical neurons and social withdrawal, deficits in nesting, and anhedonia-like behavior. Additionally, hSELENBP1 Tg mice exhibited reduced excitabilities of PFC 2/3-layer pyramidal neurons and abnormalities in EEG biomarkers observed in schizophrenia. Furthermore, mice overexpressing Selenbp1 in FC showed deficits in sociability. These results suggest that upregulation of SELENBP1 in the PFC causes asociality, a negative symptom of schizophrenia.


Assuntos
Esquizofrenia , Humanos , Animais , Camundongos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Córtex Pré-Frontal/metabolismo , Células Piramidais/metabolismo , Encéfalo/metabolismo , Camundongos Transgênicos , Proteínas de Ligação a Selênio/genética , Proteínas de Ligação a Selênio/metabolismo
2.
J Clin Psychol ; 79(12): 2768-2780, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37539866

RESUMO

INTRODUCTION: Suicide premeditation is a critical factor to consider when assessing suicide risk. Understanding which individuals are more or less likely to plan their suicidal behavior can shed light on how suicidal thoughts turn into actions. METHOD: The present study used psychological autopsy data to identify factors associated with level of premeditation among 131 adults who died by suicide. RESULTS: Logistic regression analyses indicated that suicide decedents with higher premeditation scores had higher odds of being diagnosed with a depressive disorder and choosing a violent suicide method, specifically a firearm. Individuals with lower premeditation scores had higher odds of being diagnosed with a polysubstance use disorder. CONCLUSION: Suicide decedents exhibiting greater premeditation before their deaths were different in several ways from suicide decedents exhibiting less premeditation. A better understanding of suicide premeditation can ultimately aid in the development of improved risk assessments and targeted safety interventions for those struggling with suicidal thoughts.


Assuntos
Armas de Fogo , Suicídio , Adulto , Humanos , Suicídio/psicologia , Ideação Suicida , Medição de Risco , Violência
3.
J Clin Psychol ; 78(4): 526-543, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34331770

RESUMO

OBJECTIVES: This study aimed to identify variables that distinguish suicide risk among individuals with previous suicide attempts. METHOD: Using psychological autopsy procedures, we evaluated 86 decedents who had at least one lifetime suicide attempt before eventual death by suicide (n = 65) or natural causes (n = 21). RESULTS: The Suicide Death group was more likely to be male, to have alcohol in the toxicology report at time of death, and to have a depression diagnosis, while the Natural Cause Death group was more likely to have personality disorder traits, a polysubstance use disorder, higher reported health stress, and an antidepressant in the toxicology report at time of death. Hopelessness and ambivalence were found to distinguish between groups during the 6 months before death. CONCLUSIONS: These findings suggest important differences between individuals with a shared history of a suicide attempt who die by suicide versus natural causes.


Assuntos
Autoimagem , Tentativa de Suicídio , Feminino , Humanos , Masculino , Fatores de Risco , Tentativa de Suicídio/psicologia
4.
J Neurosci ; 40(22): 4418-4431, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32269106

RESUMO

Emerging evidence suggests that there is a reduction in overall cortical excitatory to inhibitory balance in major depressive disorder (MDD), which afflicts ∼14%-20% of individuals. Reduced pyramidal cell arborization occurs with stress and MDD, and may diminish excitatory neurotransmission. Enhanced deposition of perineuronal net (PNN) components also occurs with stress. Since parvalbumin-expressing interneurons are the predominant cell population that is enveloped by PNNs, which enhance their ability to release GABA, excess PNN deposition likely increases pyramidal cell inhibition. In the present study, we investigate the potential for matrix metalloprotease-9 (MMP-9), an endopeptidase secreted in response to neuronal activity, to contribute to the antidepressant efficacy of the serotonin/norepinephrine reuptake inhibitor venlafaxine in male mice. Chronic venlafaxine increases MMP-9 levels in murine cortex, and increases both pyramidal cell arborization and PSD-95 expression in the cortex of WT but not MMP-9-null mice. We have previously shown that venlafaxine reduces PNN deposition and increases the power of ex vivo γ oscillations in conventionally housed mice. γ power is increased with pyramidal cell disinhibition and with remission from MDD. Herein we observe that PNN expression is increased in a corticosterone-induced stress model of disease and reduced by venlafaxine. Compared with mice that receive concurrent venlafaxine, corticosterone-treated mice also display reduced ex vivo γ power and impaired working memory. Autopsy-derived PFC samples show elevated MMP-9 levels in antidepressant-treated MDD patients compared with controls. These preclinical and postmortem findings highlight a link between extracellular matrix regulation and MDD.SIGNIFICANCE STATEMENT Reduced excitatory neurotransmission occurs with major depressive disorder, and may be normalized by antidepressant treatment. Underlying molecular mechanisms are, however, not well understood. Herein we investigate a potential role for an extracellular protease, released from neurons and known to play a role in learning and memory, in antidepressant-associated increases in excitatory transmission. Our data suggest that this protease, matrix metalloprotease-9, increases branching of excitatory neurons and concomitantly attenuates the perineuronal net to potentially reduce inhibitory input to these neurons. Matrix metalloprotease-9 may thus enhance overall excitatory/inhibitory balance and neuronal population dynamics, which are important to mood and memory.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Ritmo Gama , Metaloproteinase 9 da Matriz/metabolismo , Inibição Neural , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Estresse Psicológico/complicações , Cloridrato de Venlafaxina/farmacologia , Adulto , Idoso , Animais , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Transtorno Depressivo Maior/etiologia , Feminino , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Memória de Curto Prazo , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Células Piramidais/metabolismo , Células Piramidais/patologia , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico
6.
Int J Psychiatry Med ; 56(6): 408-421, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33322985

RESUMO

OBJECTIVE: The present study aimed to understand how key risk factors of older adult suicide interact to ultimately lead to death by suicide using data collected post-mortem. METHOD: A psychological autopsy was used to gather detailed information about psychiatric diagnosis, medical problems, social isolation, and negative attitudes expressed by the individual during the six months prior to their death. Interviews with next-of-kin, medical and psychiatric records, and the Cumulative Illness Rating Scale for Geriatrics were used. Subjects included 32 older adults who died by suicide and 45 older adults who died by natural causes. RESULTS: Hopelessness, depression, and negative health attitudes were strongly correlated with suicide. Older age was associated with social isolation, suggesting an indirect relationship with suicide via hopelessness, depression, and negative health attitudes. Physical illness did not increase risk. Multivariate analyses suggested that hopelessness fully mediated the effects of social isolation, negative health attitudes, and depression on suicide. CONCLUSIONS: Psychological factors played the largest role in suicide deaths compared to social isolation and physical illness. Suicide interventions aimed at older adults should ensure hopelessness, depression, and negative health attitudes are primary targets.


Assuntos
Transtornos Mentais , Suicídio , Idoso , Humanos , Fatores de Risco , Autoimagem , Isolamento Social
7.
Mol Psychiatry ; 24(3): 338-344, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30531935

RESUMO

Fragile X syndrome is rare but a prominent cause of intellectual disability. It is usually caused by a de novo mutation that occurs on multiple haplotypes and thus would not be expected to be detectible using genome-wide association (GWA). We conducted GWA in 89 male FXS cases and 266 male controls, and detected multiple genome-wide significant signals near FMR1 (odds ratio = 8.10, P = 2.5 × 10-10). These findings withstood robust attempts at falsification. Fine-mapping yielded a minimum P = 1.13 × 10-14, but did not narrow the interval. Comprehensive functional genomic integration did not provide a mechanistic hypothesis. Controls carrying a risk haplotype had significantly longer FMR1 CGG repeats than controls with the protective haplotype (P = 4.75 × 10-5), which may predispose toward increases in CGG number to the premutation range over many generations. This is a salutary reminder of the complexity of even "simple" monogenetic disorders.


Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Adulto , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Haplótipos/genética , Humanos , Deficiência Intelectual/genética , Masculino , Mutação , Fatores de Risco
8.
J Psychiatry Neurosci ; 45(5): 344-355, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32459080

RESUMO

Background: Altered function of serotonin receptor 1A (5-HT1AR) has been consistently implicated in anxiety, major depressive disorder and resistance to antidepressants. Mechanisms by which the function of 5-HT1AR (expressed as an autoreceptor in serotonergic raphe neurons and as a heteroreceptor in serotonin [5-HT] projection areas) is altered include regulation of its expression, but 5-HT1AR trafficking may also be involved. Methods: We investigated the consequences of the lack of Yif1B (the 5-HT1AR trafficking protein) on 5-HT neurotransmission in mice, and whether Yif1B expression might be affected under conditions known to alter 5-HT neurotransmission, such as anxious or depressive states or following treatment with fluoxetine (a selective serotonin reuptake inhibitor) in humans, monkeys and mice. Results: Compared with wild-type mice, Yif1B-knockout mice showed a significant decrease in the forebrain density of 5-HT projection fibres and a hypofunctionality of 5-HT1A autoreceptors expressed on raphe 5-HT neurons. In addition, social interaction was less in Yif1B-knockout mice, which did not respond to the antidepressant-like effect of acute fluoxetine injection. In wild-type mice, social defeat was associated with downregulated Yif1B mRNA in the prefrontal cortex, and chronic fluoxetine treatment increased Yif1B expression. The expression of Yif1B was also downregulated in the postmortem prefrontal cortex of people with major depressive disorder and upregulated after chronic treatment with a selective serotonin reuptake inhibitor in monkeys. Limitations: We found sex differences in Yif1B expression in humans and monkeys, but not in mice under the tested conditions. Conclusion: These data support the concept that Yif1B plays a critical role in 5-HT1AR functioning and brain 5-HT homeostasis. The opposite changes in its expression observed in anxious or depressive states and after therapeutic fluoxetine treatment suggest that Yif1B might be involved in vulnerability to anxiety and depression, and fluoxetine efficacy.


Assuntos
Transtorno Depressivo Maior/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/metabolismo , Comportamento Social , Proteínas de Transporte Vesicular/efeitos dos fármacos , Proteínas de Transporte Vesicular/metabolismo , Animais , Autopsia , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Feminino , Fluoxetina/farmacologia , Humanos , Macaca mulatta , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/fisiologia , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/fisiologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Caracteres Sexuais
9.
J Neurosci ; 38(38): 8200-8210, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30093565

RESUMO

The serotonin-1A (5-HT1A) receptor is a key regulator of serotonergic activity and is implicated in mood and emotion. However, its post-transcriptional regulation has never been studied in humans. In the present study, we show that the "intronless" human 5-HT1A gene (HTR1A) is alternatively spliced in its 3'-UTR, yielding two novel splice variants. These variants lack a ∼1.6 kb intron, which contains an microRNA-135 (miR135) target site. Unlike the human HTR1A, the mouse HTR1A lacks the splice donor/accepter sites. Thus, in the mouse HTR1A, splicing was not detected. The two spliced mRNAs are extremely stable, are resistant to miR135-induced downregulation, and have greater translational output than the unspliced variant. Moreover, alternative HTR1A RNA splicing is oppositely regulated by the splice factors PTBP1 and nSR100, which inhibit or enhance its splicing, respectively. In postmortem human brain tissue from both sexes, HTR1A mRNA splicing was prevalent and region-specific. Unspliced HTR1A was expressed more strongly in the hippocampus and midbrain versus the prefrontal cortex (PFC), and correlated with reduced levels of nSR100. Importantly, HTR1A RNA splicing and nSR100 levels were reduced in the PFC of individuals with major depression compared with controls. Our unexpected findings uncover a novel mechanism to regulate HTR1A gene expression through alternative splicing of microRNA sites. Altered levels of splice factors could contribute to changes in regional and depression-related gene expression through alternative splicing.SIGNIFICANCE STATEMENT Alternative splicing, which is prevalent in brain tissue, increases gene diversity. The serotonin-1A receptor gene (HTR1A) is a regulator of serotonin, which is implicated in mood and emotion. Here we show that human HTR1A RNA is alternately spliced. Splicing removes a microRNA site to generate ultrastable RNA and increase HTR1A expression. This splicing varies in different brain regions and is reduced in major depression. We also identify specific splice factors for HTR1A RNA, showing they are also reduced in depression. Thus, we describe a novel mechanism to regulate gene expression through splicing. Altered levels of splice factors could contribute to depression by changing gene expression.


Assuntos
Processamento Alternativo , Transtorno Depressivo Maior/metabolismo , Hipocampo/metabolismo , Mesencéfalo/metabolismo , Estabilidade de RNA/fisiologia , Receptor 5-HT1A de Serotonina/metabolismo , Adulto , Transtorno Depressivo Maior/genética , Feminino , Células HEK293 , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Receptor 5-HT1A de Serotonina/genética
10.
Neurobiol Learn Mem ; 161: 106-114, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30954674

RESUMO

We have previously reported cognitive impairments in both young and old mice, particularly in female mice expressing mouse Arg-61 apoE, with a point mutation to mimic the domain interaction feature of human apoE4, as compared to the wildtype mouse (C57BL/6J) apoE. In this study, we further evaluated water maze performance in the female Arg-61 mice at an additional time point and then investigated related hippocampal cyto-architecture in these young female Arg-61 apoE mice vs. the wildtype mice. The results of behavioral performance consistently support our previous report that the young female Arg-61 apoE showed cognitive impairment versus C57BL/6J at the same age. The cyto-architectural results showed that volume of the granular cell layer (GCL) was significantly larger in both 5- and 10-month old Arg-61 apoE mice versus C57BL/6J mice. While the number of newborn calretinin-positive neurons was greater in the sub-granular zone (SGZ) in 5-month old Arg-61 mice, this number dropped significantly in 10-month old Arg-61 mice to a lower level than in age-matched C57BL/6J mice. In addition, the amyloid ß species was significantly higher in 5-month old Arg-61 mice versus age-matched C57BL/6J mice. In conclusion, impaired cognitive functions in female Arg-61 apoE mice appear correlated with larger GCL volume and higher calretinin-positive cell number and suggest a compensatory cellular response that may be related to amyloid beta perturbations early in life. Therefore this study suggests a novel cyto-architectural mechanism of apoE4-dependent pathologies and increased susceptibility of APOEε4 subjects to Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Calbindina 2/metabolismo , Disfunção Cognitiva , Hipocampo , Neurogênese , Fatores Etários , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Comportamento Animal/fisiologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Feminino , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/patologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/genética , Neurogênese/fisiologia , Memória Espacial/fisiologia
11.
Int J Neuropsychopharmacol ; 20(5): 363-373, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28034960

RESUMO

Background: Pathology of white matter in brains of patients with major depressive disorder (MDD) is well-documented, but the cellular and molecular basis of this pathology are poorly understood. Methods: Levels of DNA oxidation and gene expression of DNA damage repair enzymes were measured in Brodmann area 10 (BA10) and/or amygdala (uncinate fasciculus) white matter tissue from brains of MDD (n=10) and psychiatrically normal control donors (n=13). DNA oxidation was also measured in BA10 white matter of schizophrenia donors (n=10) and in prefrontal cortical white matter from control rats (n=8) and rats with repeated stress-induced anhedonia (n=8). Results: DNA oxidation in BA10 white matter was robustly elevated in MDD as compared to control donors, with a smaller elevation occurring in schizophrenia donors. DNA oxidation levels in psychiatrically affected donors that died by suicide did not significantly differ from DNA oxidation levels in psychiatrically affected donors dying by other causes (non-suicide). Gene expression levels of two base excision repair enzymes, PARP1 and OGG1, were robustly elevated in oligodendrocytes laser captured from BA10 and amygdala white matter of MDD donors, with smaller but significant elevations of these gene expressions in astrocytes. In rats, repeated stress-induced anhedonia, as measured by a reduction in sucrose preference, was associated with increased DNA oxidation in white, but not gray, matter. Conclusions: Cellular residents of brain white matter demonstrate markers of oxidative damage in MDD. Medications that interfere with oxidative damage or pathways activated by oxidative damage have potential to improve treatment for MDD.


Assuntos
DNA Glicosilases/metabolismo , Desoxiguanosina/análogos & derivados , Transtorno Depressivo Maior/patologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Substância Branca/enzimologia , 8-Hidroxi-2'-Desoxiguanosina , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Astrócitos/metabolismo , Desoxiguanosina/metabolismo , Transtorno Depressivo Maior/psicologia , Modelos Animais de Doenças , Feminino , Humanos , Relações Interpessoais , Masculino , Pessoa de Meia-Idade , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Ratos , Ratos Sprague-Dawley , Esquizofrenia/patologia , Adulto Jovem
12.
Biochim Biophys Acta Gen Subj ; 1861(2): 246-255, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27838394

RESUMO

BACKGROUND: Neuropeptide precursors are traditionally viewed as proteins giving rise to small neuropeptide molecules. Prodynorphin (PDYN) is the precursor protein to dynorphins, endogenous ligands for the κ-opioid receptor. Alternative mRNA splicing of neuropeptide genes may regulate cell- and tissue-specific neuropeptide expression and produce novel protein isoforms. We here searched for novel PDYN mRNA and their protein product in the human brain. METHODS: Novel PDYN transcripts were identified using nested PCR amplification of oligo(dT) selected full-length capped mRNA. Gene expression was analyzed by qRT-PCR, PDYN protein by western blotting and confocal imaging, dynorphin peptides by radioimmunoassay. Neuronal nuclei were isolated using fluorescence-activated nuclei sorting (FANS) from postmortem human striatal tissue. Immunofluorescence staining and confocal microscopy was performed for human caudate nucleus. RESULTS: Two novel human PDYN mRNA splicing variants were identified. Expression of one of them was confined to the striatum where its levels constituted up to 30% of total PDYN mRNA. This transcript may be translated into ∆SP-PDYN protein lacking 13 N-terminal amino acids, a fragment of signal peptide (SP). ∆SP-PDYN was not processed to mature dynorphins and surprisingly, was targeted to the cell nuclei in a model cellular system. The endogenous PDYN protein was identified in the cell nuclei in human striatum by western blotting of isolated neuronal nuclei, and by confocal imaging. CONCLUSIONS AND GENERAL SIGNIFICANCE: High levels of alternatively spliced ∆SP-PDYN mRNA and nuclear localization of PDYN protein suggests a nuclear function for this isoform of the opioid peptide precursor in human striatum.


Assuntos
Núcleo Caudado/metabolismo , Núcleo Celular/metabolismo , Peptídeos Opioides/metabolismo , Isoformas de Proteínas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoácidos/metabolismo , Animais , Linhagem Celular Tumoral , Dinorfinas/metabolismo , Encefalinas/metabolismo , Feminino , Regulação da Expressão Gênica/fisiologia , Inativação Gênica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Precursores de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Adulto Jovem
13.
Bipolar Disord ; 18(1): 41-51, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26842627

RESUMO

OBJECTIVES: Neuroimaging studies have revealed lithium-related increases in the volume of gray matter in the prefrontal cortex (PFC) and hippocampus. Postmortem human studies have reported alterations in neuronal and glial cell density and size in the PFC of lithium-treated subjects. Rodents treated with lithium exhibit cell proliferation in the dentate gyrus (DG) of the hippocampus. However, it is not known whether hippocampal and PFC volume are also increased in these animals or whether cell number in the PFC is altered. METHODS: Using stereological methods, this study estimated the total numbers of neurons and glia, and the packing density of astrocytes in the DG and PFC of normal adult mice treated with lithium, and evaluated the total volume of these regions and the entire neocortex. RESULTS: Lithium treatment increased the total numbers of neurons and glia in the DG (by 25% and 21%, respectively) and the density of astrocytes but did not alter total numbers in the PFC. However, the volumes of the hippocampus and its subfields, the PFC and its subareas, and the entire neocortex were not altered by lithium. CONCLUSIONS: Both neuronal and glial cells accounted for lithium-induced cell proliferation in the DG. That the numbers of neurons and glia were unchanged in the PFC is consistent with the view that this region is not a neurogenic zone. Further studies are required to clarify the impact of lithium treatment on the PFC under pathological conditions and to investigate the dissociation between increased cell proliferation and unchanged volume in the hippocampus.


Assuntos
Astrócitos/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Compostos de Lítio/farmacologia , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Transtorno Bipolar/patologia , Contagem de Células , Giro Denteado/citologia , Giro Denteado/patologia , Hipocampo/citologia , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/patologia
14.
Alcohol Clin Exp Res ; 40(11): 2320-2328, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27647657

RESUMO

BACKGROUND: Ethanol (EtOH) neurotoxicity can result in devastating effects on brain and behavior by disrupting homeostatic signaling cascades and inducing cell death. One such mechanism involves double-stranded RNA activated protein kinase (PKR), a primary regulator of protein translation and cell viability in the presence of a virus or other external stimuli. EtOH-mediated up-regulation of interferon-gamma (IFN-γ; the oxidative stress-inducible regulator of PKR), PKR, and its target, p53, are still being fully elucidated. METHODS: Using Western blot analysis, immunofluorescence, and linear regression analyses, changes in the IFN-γ-PKR-p53 pathway following chronic EtOH treatment in the frontal cortex of rodents were examined. The role of PKR on cell viability was also assessed in EtOH-treated cells using PKR overexpression vector and PKR inhibitor (PKRI). RESULTS: In rats chronically fed EtOH, PKR, phosphorylated PKR (p-PKR), IFN-γ, and p53 were significantly increased following chronic EtOH exposure. Linear regression revealed a significant correlation between IFN-γ and p-PKR protein levels, as well as p-PKR expression and age of EtOH exposure. Overexpression of PKR resulted in greater cell death, while use of PKRI enhanced cell viability in EtOH-treated cells. CONCLUSIONS: Chronic EtOH exposure activates the IFN-γ-PKR-p53 pathway in the frontal cortex of rodents. p-PKR expression is greater in brains of rodents exposed to EtOH at earlier ages compared to later life, suggesting a mechanism by which young brains could be more susceptible to EtOH-related brain injury. PKR and p-PKR were also colocalized in neurons and astrocytes of rats. This study provides additional insight into biochemical mechanisms underlying alcohol use disorder related neuropathology and warrants further investigation of PKR as a potential pharmacotherapeutic target to combat EtOH-related neurotoxicity, loss of protein translation and brain injury.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Interferon gama/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , eIF-2 Quinase/metabolismo , Idade de Início , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Córtex Pré-Frontal/metabolismo , Distribuição Aleatória , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
15.
Mol Pharmacol ; 88(4): 640-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26162864

RESUMO

AT-1001 [N-(2-bromophenyl)-9-methyl-9-azabicyclo[3.3.1] nonan-3-amine] is a high-affinity and highly selective ligand at α3ß4 nicotinic cholinergic receptors (nAChRs) that was reported to decrease nicotine self-administration in rats. It was initially reported to be an antagonist at rat α3ß4 nAChRs heterologously expressed in HEK293 cells. Here we compared AT-1001 actions at rat and human α3ß4 and α4ß2 nAChRs similarly expressed in HEK 293 cells. We found that, as originally reported, AT-1001 is highly selective for α3ß4 receptors over α4ß2 receptors, but its binding selectivity is much greater at human than at rat receptors, because of a higher affinity at human than at rat α3ß4 nAChRs. Binding studies in human and rat brain and pineal gland confirmed the selectivity of AT-1001 for α3ß4 nAChRs and its higher affinity for human compared with rat receptors. In patch-clamp electrophysiology studies, AT-1001 was a potent partial agonist with 65-70% efficacy at both human and rat α3ß4 nAChRs. It was also a less potent and weaker (18%) partial agonist at α4ß2 nAChRs. Both α3ß4 and α4ß2 nAChRs are upregulated by exposure of cells to AT-1001 for 3 days. Similarly, AT-1001 desensitized both receptor subtypes in a concentration-dependent manner, but it was 10 and 30 times more potent to desensitize human α3ß4 receptors than rat α3ß4 and human α4ß2 receptors, respectively. After exposure to AT-1001, the time to recovery from desensitization was longest for the human α3ß4 nAChR and shortest for the human α4ß2 receptor, suggesting that recovery from desensitization is primarily related to the dissociation of the ligand from the receptor.


Assuntos
Agonismo Parcial de Drogas , Agonistas Nicotínicos/metabolismo , Oligopeptídeos/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Humanos , Masculino , Agonistas Nicotínicos/farmacologia , Oligopeptídeos/farmacologia , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie
16.
Alcohol Clin Exp Res ; 39(3): 476-84, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25704249

RESUMO

BACKGROUND: Brain cell death is a major pathological consequence of alcohol neurotoxicity. However, the molecular cascades in alcohol-induced brain tissue injury are unclear. METHODS: Using Western blot and double immunofluorescence, we examined the expression of interferon (IFN)-induced protein kinase R (PKR), phosphorylated-PKR (p-PKR), and IFN gamma (IFNγ) in the prefrontal cortex (PFC) of postmortem brains from subjects with alcohol use disorders (AUD). RESULTS: The protein levels of PKR, p-PKR, and IFNγ were significantly increased in subjects with AUD compared with control subjects without AUD, and a younger age of onset of AUD was significantly correlated with higher protein levels of p-PKR. In addition, elevated PKR- and p-PKR-IR were observed in both neurons and astrocytes in the PFC of subjects with AUD compared to subjects without AUD. CONCLUSIONS: The activation of the IFNγ-PKR pathway in PFC of humans is associated with chronic excessive ethanol use with an age of onset dependent manner, and activation of this pathway may play a pivotal role in AUD-related brain tissue injury. This study provides insight into neurodegenerative key factors related to AUD and identifies potential targets for the treatment of alcohol-induced neurotoxicity.


Assuntos
Transtornos Relacionados ao Uso de Álcool/metabolismo , Interferon gama/biossíntese , Córtex Pré-Frontal/metabolismo , Transdução de Sinais , eIF-2 Quinase/biossíntese , Adulto , Transtornos Relacionados ao Uso de Álcool/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/patologia , Transdução de Sinais/fisiologia
17.
Int J Neuropsychopharmacol ; 17(10): 1579-89, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24967945

RESUMO

Telomere shortening is observed in peripheral mononuclear cells from patients with major depressive disorder (MDD). Whether this finding and its biological causes impact the health of the brain in MDD is unknown. Brain cells have differing vulnerabilities to biological mechanisms known to play a role in accelerating telomere shortening. Here, two glia cell populations (oligodendrocytes and astrocytes) known to have different vulnerabilities to a key mediator of telomere shortening, oxidative stress, were studied. The two cell populations were separately collected by laser capture micro-dissection of two white matter regions shown previously to demonstrate pathology in MDD patients. Cells were collected from brain donors with MDD at the time of death and age-matched psychiatrically normal control donors (N = 12 donor pairs). Relative telomere lengths in white matter oligodendrocytes, but not astrocytes, from both brain regions were significantly shorter for MDD donors as compared to matched control donors. Gene expression levels of telomerase reverse transcriptase were significantly lower in white matter oligodendrocytes from MDD as compared to control donors. Likewise, the gene expression of oxidative defence enzymes superoxide dismutases (SOD1 and SOD2), catalase (CAT) and glutathione peroxidase (GPX1) were significantly lower in oligodendrocytes from MDD as compared to control donors. No such gene expression changes were observed in astrocytes from MDD donors. These findings suggest that attenuated oxidative stress defence and deficient telomerase contribute to telomere shortening in oligodendrocytes in MDD, and suggest an aetiological link between telomere shortening and white matter abnormalities previously described in MDD.


Assuntos
Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Oligodendroglia/metabolismo , Estresse Oxidativo , Telômero/metabolismo , Substância Branca/patologia , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Catalase/genética , Catalase/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Humanos , Microdissecção e Captura a Laser , Masculino , Pessoa de Meia-Idade , Análise Multivariada , RNA Mensageiro , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Telomerase/genética , Telomerase/metabolismo , Adulto Jovem
18.
Int J Neuropsychopharmacol ; 17(10): 1569-78, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24925192

RESUMO

Glutamate receptors are promising drug targets for the treatment of urgent suicide ideation and chronic major depressive disorder (MDD) that may lead to suicide completion. Antagonists of glutamatergic NMDA receptors reduce depressive symptoms faster than traditional antidepressants, with beneficial effects occurring within hours. Glutamate is the prominent excitatory input to the noradrenergic locus coeruleus (LC). The LC is activated by stress in part through this glutamatergic input. Evidence has accrued demonstrating that the LC may be overactive in MDD, while treatment with traditional antidepressants reduces LC activity. Pathological alterations of both glutamatergic and noradrenergic systems have been observed in depressive disorders, raising the prospect that disrupted glutamate-norepinephrine interactions may be a central component to depression and suicide pathobiology. This study examined the gene expression levels of glutamate receptors in post-mortem noradrenergic LC neurons from subjects with MDD (most died by suicide) and matched psychiatrically normal controls. Gene expression levels of glutamate receptors or receptor subunits were measured in LC neurons collected by laser capture microdissection. MDD subjects exhibited significantly higher expression levels of the NMDA receptor subunit genes, GRIN2B and GRIN2C, and the metabotropic receptor genes, GRM4 and GRM5, in LC neurons. Gene expression levels of these receptors in pyramidal neurons from prefrontal cortex (BA10) did not reveal abnormalities in MDD. These findings implicate disrupted glutamatergic-noradrenergic interactions at the level of the stress-sensitive LC in MDD and suicide, and provide a theoretical mechanism by which glutamate antagonists may exert rapid antidepressant effects.


Assuntos
Neurônios Adrenérgicos/metabolismo , Transtorno Depressivo Maior/patologia , Expressão Gênica/fisiologia , Locus Cerúleo/patologia , Receptores de Glutamato/metabolismo , Adolescente , Adulto , Idoso , Autopsia , Feminino , Humanos , Microdissecção e Captura a Laser , Locus Cerúleo/metabolismo , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , RNA Mensageiro/metabolismo , Receptores de Glutamato/genética
19.
Alcohol Clin Exp Res ; 38(11): 2790-9, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25421516

RESUMO

BACKGROUND: Alcohol-dependent (ALC) subjects exhibit glial and neuronal pathology in the prefrontal cortex (PFC). However, in many patients, neurophysiological disturbances are not associated with catastrophic cell depletion despite prolonged alcohol abuse. It is still unclear how some relevant markers of a cell's propensity to degenerate or proliferate are changed in the PFC of ALC subjects without major neurological disorders. METHODS: Levels of pro-apoptotic caspase 8 (C8), X-linked inhibitor of apoptosis protein (XIAP), direct IAP binding protein with low pI (DIABLO), proliferating cell nuclear antigen (PCNA), and density of cells immunoreactive for proliferation marker Ki-67 (Ki-67-IR) were measured postmortem in the left orbitofrontal cortex (OFC) of 29 subjects with alcohol dependence and 23 nonpsychiatric comparison subjects. RESULTS: Alcohol subjects had significantly higher levels of the 14 kDa C8 fragment (C8-14), an indicator of C8 activation. However, there was no change in the levels of DIABLO, XIAP, or in the DIABLO/XIAP ratio. PCNA protein level and density of Ki-67-IR cells were not significantly changed in alcoholics, although PCNA levels were increased in older ALC subjects as compared to controls. CONCLUSIONS: Significant increase of a C8 activation indicator was found in alcoholism, but without significant changes in XIAP level, DIABLO/XIAP ratio, or Ki-67 labeling. These results would help to explain the absence of catastrophic cell loss in the PFC of many Brigman subjects, while still being consistent with an alcoholism-related vulnerability to slow decline in glial cells and neurons in the OFC of alcoholics.


Assuntos
Alcoolismo/metabolismo , Alcoolismo/patologia , Apoptose/fisiologia , Proliferação de Células/fisiologia , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
20.
Alcohol Clin Exp Res ; 38(1): 144-51, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23915421

RESUMO

BACKGROUND: The biochemical pathways underlying alcohol abuse and dependence are not well understood, although brain cell loss and neurotoxicity have been reported in subjects with alcohol dependence. Monoamine oxidase B (MAO B; an enzyme that catabolizes neurotransmitters such as dopamine) is consistently increased in this psychiatric illness. MAO B has been implicated in the pathogenesis of alcohol dependence and alcohol-induced brain neurotoxicity. Recently, the cell growth inhibitor protein, Kruppel-like factor 11 (KLF11), has been reported to be an MAO transcriptional activator. KLF11 is also known as TIEG2 (transforming growth factor-beta-inducible early gene 2) and mediates apoptotic cell death. This study investigates the protein expression of KLF11 and its relationship with MAO B using human postmortem prefrontal cortex from subjects with alcohol dependence. METHODS: Twelve subjects with alcohol dependence and the respective psychiatrically normal control subjects were investigated. Expression of KLF11 and MAO B proteins in the prefrontal cortex was measured by Western blot analysis. Correlation studies involving KLF11 and MAO B protein expression were performed. Localization of KLF11 in the human prefrontal cortex was also determined by immunohistochemistry. RESULTS: Levels of KLF11 protein were significantly increased by 44% (p < 0.03) in the postmortem prefrontal cortex of subjects with alcohol dependence as compared to age- and gender-matched, psychiatrically normal control subjects. Furthermore, KLF11 levels were significantly and positively correlated with both the increased MAO B protein levels and blood alcohol content in alcohol-dependent subjects. In addition, KLF11 protein expression was visualized in both neuronal and glial cells. CONCLUSIONS: This novel study shows the important role of KLF11, an MAO transcriptional activator, in human alcohol dependence. It further supports that the KLF11-MAO B cell death cascade may contribute to chronic alcohol-induced brain damage. This argues a case for KLF11-MAO B inhibition as a novel therapeutic strategy that may impact this highly prevalent illness.


Assuntos
Alcoolismo/metabolismo , Proteínas de Ciclo Celular/biossíntese , Regulação da Expressão Gênica , Monoaminoxidase/biossíntese , Córtex Pré-Frontal/metabolismo , Proteínas Repressoras/biossíntese , Ativação Transcricional/fisiologia , Alcoolismo/patologia , Proteínas Reguladoras de Apoptose , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/patologia , Estudos Retrospectivos
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