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Background: Many patients suffering from depressive disorders are refractory to treatment with currently available antidepressant medications, while many more exhibit only a partial response. These factors drive research to discover new pharmacological approaches to treat depression. Numerous studies demonstrate evidence of inflammation and elevated oxidative stress in major depression. Recently, major depression has been shown to be associated with elevated levels of DNA oxidation in brain cells, accompanied by increased gene expression of the nuclear base excision repair enzyme, poly(ADP-ribose) polymerase-1. Given these findings and evidence that drugs that inhibit poly(ADP-ribose) polymerase-1 activity have antiinflammatory and neuroprotective properties, the present study was undertaken to examine the potential antidepressant properties of poly(ADP-ribose) polymerase inhibitors. Methods: Two rodent models, the Porsolt swim test and repeated exposure to psychological stressors, were used to test the poly(ADP-ribose) polymerase inhibitor, 3-aminobenzamide, for potential antidepressant activity. Another poly(ADP-ribose) polymerase inhibitor, 5-aminoisoquinolinone, was also tested. Results: Poly(ADP-ribose) polymerase inhibitors produced antidepressant-like effects in the Porsolt swim test, decreasing immobility time, and increasing latency to immobility, similar to the effects of fluoxetine. In addition, 3-aminobenzamide treatment increased sucrose preference and social interaction times relative to vehicle-treated control rats following repeated exposure to combined social defeat and unpredictable stress, mediating effects similar to fluoxetine treatment. Conclusions: The poly(ADP-ribose) polymerase inhibitors 3-aminobenzamide and 5-aminoisoquinolinone exhibit antidepressant-like activity in 2 rodent stress models and uncover poly(ADP-ribose) polymerase as a unique molecular target for the potential development of a novel class of antidepressants.
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Antidepresivos/uso terapéutico , Modelos Animales de Enfermedad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Estrés Psicológico/tratamiento farmacológico , Animales , Benzamidas/uso terapéutico , Relación Dosis-Respuesta a Droga , Fluoxetina/uso terapéutico , Preferencias Alimentarias/efectos de los fármacos , Pérdida de Tono Postural/efectos de los fármacos , Relaciones Interpersonales , Isoquinolinas/uso terapéutico , Masculino , Ratas , Tiempo de Reacción/efectos de los fármacos , Sacarosa/administración & dosificación , Natación/psicologíaRESUMEN
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.
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ADN Glicosilasas/metabolismo , Desoxiguanosina/análogos & derivados , Trastorno Depresivo Mayor/patología , Regulación Enzimológica de la Expresión Génica/fisiología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Sustancia Blanca/enzimología , 8-Hidroxi-2'-Desoxicoguanosina , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Astrocitos/metabolismo , Desoxiguanosina/metabolismo , Trastorno Depresivo Mayor/psicología , Modelos Animales de Enfermedad , Femenino , Humanos , Relaciones Interpersonales , Masculino , Persona de Mediana Edad , Oligodendroglía/metabolismo , Oligodendroglía/patología , Ratas , Ratas Sprague-Dawley , Esquizofrenia/patología , Adulto JovenRESUMEN
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.
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Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/patología , Oligodendroglía/metabolismo , Estrés Oxidativo , Telómero/metabolismo , Sustancia Blanca/patología , 2',3'-Nucleótido Cíclico 3'-Fosfodiesterasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Catalasa/genética , Catalasa/metabolismo , Femenino , Regulación de la Expresión Génica/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Humanos , Captura por Microdisección con Láser , Masculino , Persona de Mediana Edad , Análisis Multivariante , ARN Mensajero , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1 , Telomerasa/genética , Telomerasa/metabolismo , Adulto JovenRESUMEN
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.
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Neuronas Adrenérgicas/metabolismo , Trastorno Depresivo Mayor/patología , Expresión Génica/fisiología , Locus Coeruleus/patología , Receptores de Glutamato/metabolismo , Adolescente , Adulto , Anciano , Autopsia , Femenino , Humanos , Captura por Microdisección con Láser , Locus Coeruleus/metabolismo , Masculino , Persona de Mediana Edad , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , ARN Mensajero/metabolismo , Receptores de Glutamato/genéticaRESUMEN
BACKGROUND: Myocardial ischemia causes the release of bradykinin, which stimulates cardiac afferents, causing sympathetic excitation and chest pain. Glutamatergic activation of the paraventricular hypothalamic nucleus (PVN) in the spontaneously hypertensive rat (SHR) drives elevated basal sympathetic activity. Thus, we tested the hypothesis that inactivation of the PVN attenuates the elevated reflex response to epicardial bradykinin in the SHR and that ionotropic PVN glutamate receptors mediate the elevated reflex. METHODS: We recorded the arterial pressure and renal sympathetic nerve activity (RSNA) response to epicardial bradykinin application in anesthetized SHR and Wistar Kyoto (WKY) rats before and after PVN microinjection of GABA A agonist muscimol or ionotropic glutamate receptor antagonist kynurenic acid. RESULTS: Muscimol significantly decreased the arterial pressure response to bradykinin from 180.4â±â5.8 to 119.5â±â6.9âmmHg in the SHR and from 111.8â±â7.0 to 84.2â±â8.3âmmHg in the WKY and the RSNA response from 186.2â±â7.1 to 142.7â±â7.3% of baseline in the SHR and from 201.0â±â11.5 to 160.2â±â9.3% of baseline in the WKY. Kynurenic acid significantly decreased the arterial pressure response in the SHR from 164.5â±â5.0 to 126.2â±â7.7âmmHg and the RSNA response from 189.9â±â13.7to 168.5â±â12.7% of baseline but had no effect in the WKY. CONCLUSION: These results suggest that tonic PVN activity is critical for the full manifestation of the CSAR in both the WKY and SHR. Glutamatergic PVN activity contributes to the augmented CSAR observed in the SHR.
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Bradiquinina , Núcleo Hipotalámico Paraventricular , Ratas , Animales , Ratas Endogámicas SHR , Bradiquinina/farmacología , Ratas Endogámicas WKY , Ácido Quinurénico/farmacología , Muscimol/farmacología , Reflejo/fisiología , Sistema Nervioso Simpático , Presión SanguíneaRESUMEN
BACKGROUND: Norepinephrine and glutamate are among several neurotransmitters implicated in the neuropathology of major depressive disorder (MDD). Glia deficits have also been demonstrated in people with MDD, and glia are critical modulators of central glutamatergic transmission. We studied glia in men with MDD in the region of the brain (locus coeruleus; LC) where noradrenergic neuronal cell bodies reside and receive glutamatergic input. METHODS: The expression of 3 glutamate-related genes (SLC1A3, SLC1A2, GLUL) concentrated in glia and a glia gene (GFAP) were measured in postmortem tissues from men with MDD and from paired psychiatrically healthy controls. Initial gene expression analysis of RNA isolated from homogenized tissue (n = 9-10 pairs) containing the LC were followed by detailed analysis of gene expressions in astrocytes and oligodendrocytes (n = 6-7 pairs) laser captured from the LC region. We assessed protein changes in GFAP using immunohistochemistry and immunoblotting (n = 7-14 pairs). RESULTS: Astrocytes, but not oligodendrocytes, demonstrated robust reductions in the expression of SLC1A3 and SLC1A2, whereas GLUL expression was unchanged. GFAP expression was lower in astrocytes, and we confirmed reduced GFAP protein in the LC using immunostaining methods. LIMITATIONS: Reduced expression of protein products of SLC1A3 and SLC1A2 could not be confirmed because of insufficient amounts of LC tissue for these assays. Whether gene expression abnormalities were associated with only MDD and not with suicide could not be confirmed because most of the decedents who had MDD died by suicide. CONCLUSION: Major depressive disorder is associated with unhealthy astrocytes in the noradrenergic LC, characterized here by a reduction in astrocyte glutamate transporter expression. These findings suggest that increased glutamatergic activity in the LC occurs in men with MDD.
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Astrocitos/metabolismo , Trastorno Depresivo Mayor/genética , Predisposición Genética a la Enfermedad/genética , Locus Coeruleus/metabolismo , Oligodendroglía/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Trastorno Depresivo Mayor/metabolismo , Transportador 1 de Aminoácidos Excitadores/biosíntesis , Transportador 2 de Aminoácidos Excitadores , Expresión Génica , Proteína Ácida Fibrilar de la Glía/biosíntesis , Proteínas de Transporte de Glutamato en la Membrana Plasmática/biosíntesis , Glutamato-Amoníaco Ligasa/biosíntesis , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The noradrenergic locus coeruleus (LC) is the principal source of brain norepinephrine, a neurotransmitter thought to play a major role in the pathology of major depressive disorder (MDD) and in the therapeutic action of many antidepressant drugs. The goal of this study was to identify potential mediators of brain noradrenergic dysfunction in MDD. Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor-ß superfamily, is a critical mediator of noradrenergic neuron differentiation during development and has neurotrophic and neuroprotective effects on mature catecholaminergic neurons. Real-time PCR of reversed transcribed RNA isolated from homogenates of LC tissue from 12 matched pairs of MDD subjects and psychiatrically normal control subjects revealed low levels of BMP7 gene expression in MDD. No differences in gene expression levels of other members of the BMP family were observed in the LC, and BMP7 gene expression was normal in the prefrontal cortex and amygdala in MDD subjects. Laser capture microdissection of noradrenergic neurons, astrocytes, and oligodendrocytes from the LC revealed that BMP7 gene expression was highest in LC astrocytes relative to the other cell types, and that the MDD-associated reduction in BMP7 gene expression was limited to astrocytes. Rats exposed to chronic social defeat exhibited a similar reduction in BMP7 gene expression in the LC. BMP7 has unique developmental and trophic actions on catecholamine neurons and these findings suggest that reduced astrocyte support for pontine LC neurons may contribute to pathology of brain noradrenergic neurons in MDD.
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Astrocitos/metabolismo , Proteína Morfogenética Ósea 7/metabolismo , Trastorno Depresivo Mayor/patología , Regulación de la Expresión Génica/fisiología , Locus Coeruleus/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Proteína Morfogenética Ósea 7/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Masculino , Microdisección , Persona de Mediana Edad , Ratas , Estudios Retrospectivos , Tirosina 3-Monooxigenasa/metabolismo , Adulto JovenRESUMEN
Major depressive disorder (MDD) and suicide have been associated with elevated indices of oxidative damage in the brain, as well as white matter pathology including reduced myelination by oligodendrocytes. Oligodendrocytes highly populate white matter and are inherently susceptible to oxidative damage. Pathology of white matter oligodendrocytes has been reported to occur in brain regions that process behaviors that are disrupted in MDD and that may contribute to suicidal behavior. The present study was designed to determine whether oligodendrocyte pathology related to oxidative damage extends to brain areas outside of those that are traditionally considered to contribute to the psychopathology of MDD and suicide. Relative telomere lengths and the gene expression of five antioxidant-related genes, SOD1, SOD2, GPX1, CAT, and AGPS were measured in oligodendrocytes laser captured from two non-limbic brain areas: occipital cortical white matter and the brainstem locus coeruleus. Postmortem brain tissues were obtained from brain donors that died by suicide and had an active MDD at the time of death, and from psychiatrically normal control donors. Relative telomere lengths were significantly reduced in oligodendrocytes of both brain regions in MDD donors as compared to control donors. Three antioxidant-related genes (SOD1, SOD2, GPX1) were significantly reduced and one was significantly elevated (AGPS) in oligodendrocytes from both brain regions in MDD as compared to control donors. These findings suggest that oligodendrocyte pathology in MDD and suicide is widespread in the brain and not restricted to brain areas commonly associated with depression psychopathology.
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Trastorno Depresivo Mayor , Suicidio , Antioxidantes/metabolismo , Trastorno Depresivo Mayor/metabolismo , Humanos , Locus Coeruleus/metabolismo , Lóbulo Occipital , Oligodendroglía/metabolismo , Estrés Oxidativo , Superóxido Dismutasa-1/metabolismoRESUMEN
Evidence for putative pathophysiological mechanisms of autism spectrum disorder (ASD), including peripheral inflammation, blood-brain barrier disruption, white matter alterations, and abnormal synaptic overgrowth, indicate a possible involvement of neuroinflammation in the disorder. Neuroinflammation plays a role in the development and maintenance of the dendritic spines involved in glutamatergic and GABAergic neurotransmission, and also influences blood-brain permeability. Cytokines released from microglia can impact the length, location or organization of dendritic spines on excitatory and inhibitory cells as well as recruit and impact glial cell function around the neurons. In this study, gene expression levels of anti- and pro-inflammatory signaling molecules, as well as oligodendrocyte and astrocyte marker proteins, were measured in both gray and white matter tissue in the anterior cingulate cortex from ASD and age-matched typically developing (TD) control brain donors, ranging from ages 4 to 37 years. Expression levels of the pro-inflammatory gene, HLA-DR, were significantly reduced in gray matter and expression levels of the anti-inflammatory gene MRC1 were significantly elevated in white matter from ASD donors as compared to TD donors, but neither retained statistical significance after correction for multiple comparisons. Modest trends toward differences in expression levels were also observed for the pro-inflammatory (CD68, IL1ß) and anti-inflammatory genes (IGF1, IGF1R) comparing ASD donors to TD donors. The direction of gene expression changes comparing ASD to TD donors did not reveal consistent findings implicating an elevated pro- or anti-inflammatory state in ASD. However, altered expression of pro- and anti-inflammatory gene expression indicates some involvement of neuroinflammation in ASD. Autism Res 2020, 13: 870-884. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The anterior cingulate cortex is an integral brain region in modulating social behaviors including nonverbal communication. The study found that inflammatory gene expression levels were altered in this brain region. We hypothesize that the inflammatory changes in this area could impact neuronal function. The finding has future implications in using these molecular markers to identify potential environmental exposures and distinct cell differences in autism.
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Trastorno del Espectro Autista/genética , Regulación de la Expresión Génica , Sustancia Gris/metabolismo , Giro del Cíngulo/metabolismo , Inflamación/genética , Sustancia Blanca/metabolismo , Adolescente , Adulto , Niño , Humanos , Masculino , Adulto JovenRESUMEN
One of the etiological theories of schizophrenia is dysregulation of the immune system. Autoantibodies specific for the alpha7 subunit of the nicotinic receptor could potentially contribute to the pathophysiology of the disease. In this study, positive antibodies specific for the receptor were found to exist in 23% of the patients diagnosed with schizophrenia (n=21). On the average, levels for the antibody were elevated in the schizophrenia patient population than in controls. The data also suggests that there is a significant correlation between antibody titer and age, lending support to the neurodegenerative nature of the disease.
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Anticuerpos/sangre , Receptores Nicotínicos/inmunología , Esquizofrenia/sangre , Esquizofrenia/inmunología , Factores de Edad , Anciano , Autoanticuerpos/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores Nicotínicos/sangreRESUMEN
BACKGROUND: The anterior cingulate cortex (ACC) is a brain area involved in modulating behavior associated with social interaction, disruption of which is a core feature of autism spectrum disorder (ASD). Functional brain imaging studies demonstrate abnormalities of the ACC in ASD as compared to typically developing control patients. However, little is known regarding the cellular basis of these functional deficits in ASD. Pyramidal neurons in the ACC are excitatory glutamatergic neurons and key cellular mediators of the neural output of the ACC. This study was designed to investigate the potential role of ACC pyramidal neurons in ASD brain pathology. METHODS: Postmortem ACC tissue from carefully matched ASD and typically developing control donors was obtained from two national brain collections. Pyramidal neurons and surrounding astrocytes were separately collected from layer III of the ACC by laser capture microdissection. Isolated RNA was subjected to reverse transcription and endpoint PCR to determine gene expression levels for 16 synaptic genes relevant to glutamatergic neurotransmission. Cells were also collected from the prefrontal cortex (Brodmann area 10) to examine those genes demonstrating differences in expression in the ACC comparing typically developing and ASD donors. RESULTS: The level of NTRK2 expression was robustly and significantly lower in pyramidal neurons from ASD donors as compared to typically developing donors. Levels of expression of GRIN1, GRM8, SLC1A1, and GRIP1 were modestly lower in pyramidal neurons from ASD donors, but statistical significance for these latter genes did not survive correction for multiple comparisons. No significant expression differences of any genes were found in astrocytes laser captured from the same neocortical area. In addition, expression levels of NTRK2 and other synaptic genes were normal in pyramidal neurons laser captured from the prefrontal cortex. CONCLUSIONS: These studies demonstrate a unique pathology of neocortical pyramidal neurons of the ACC in ASD. NTRK2 encodes the tropomyosin receptor kinase B (TrkB), transmission through which neurotrophic factors modify differentiation, plasticity, and synaptic transmission. Reduced pyramidal neuron NTRK2 expression in the ACC could thereby contribute to abnormal neuronal activity and disrupt social behavior mediated by this brain region.
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[This corrects the article DOI: 10.1186/s13229-015-0023-2.].
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Based on evidence of abnormalities in axon thickness and neuronal disorganization, autism spectrum disorder (ASD) is commonly considered to be a condition resulting from neuronal dysfunction. Yet, recent findings suggest that non-neuronal cell types also contribute to ASD pathology. To investigate the role of glial cells in ASD, a combination of protein and gene expression analyses were used to determine levels of two glial markers, glial fibrillary acidic protein (GFAP) and myelin oligodendrocyte glycoprotein (MOG), in the postmortem brain tissue from control and ASD donors. Levels of GFAP immunoreactivity (ir) were significantly elevated (P = 0.008) in anterior cingulate cortex (Brodmann area 24; BA24) white matter of ASD donors compared to control donors. In contrast, GFAP-ir levels were similar in BA24 gray matter from ASD and control donors. MOG-ir was also similar in both BA24 white and gray matter from ASD and control donors. In anterior prefrontal cortex (BA10), there were no significant differences in GFAP-ir or MOG-ir in either white or gray matter comparing ASD to control donors. Levels of expression of the genes GFAP and MOG also showed no differences between control and ASD donors in BA24 and BA10 white and gray matter. Collectively, these data imply that ASD is associated with an activation of white matter astrocytes in the anterior cingulate cortex as a result of a yet undefined cellular insult. Research is needed to investigate the molecular pathways that underlie this astrocyte reaction and such research may yield important clues regarding the etiology of ASD.