RESUMO
Studies of genetics, serum cytokines, and autoimmune illnesses suggest that immune-related abnormalities are involved in the disease process of schizophrenia. Furthermore, direct evidence of cortical immune activation, including markedly elevated levels of many immune-related markers, have been reported in the prefrontal cortex in multiple cohorts of schizophrenia subjects. Within the prefrontal cortex in schizophrenia, deficits in the basilar dendritic spines of layer 3 pyramidal neurons and disturbances in inhibitory inputs to pyramidal neurons have also been commonly reported. Interestingly, microglia, the resident immune-related cells of the brain, also regulate excitatory and inhibitory input to pyramidal neurons. Consequently, in this review, we describe the cytological and molecular evidence of immune activation that has been reported in the brains of individuals with schizophrenia and the potential links between these immune-related disturbances with previously reported disturbances in pyramidal and inhibitory neurons in the disorder. Finally, we discuss the role that activated microglia may play in connecting these observations and as potential therapeutic treatment targets in schizophrenia.
Assuntos
Microglia/metabolismo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/metabolismo , Animais , Humanos , Microglia/patologia , Vias Neurais/metabolismo , Vias Neurais/patologia , Córtex Pré-Frontal/patologia , Esquizofrenia/epidemiologia , Esquizofrenia/patologiaRESUMO
Markers of GABA neurotransmission are altered in multiple regions of the neocortex in individuals with schizophrenia. Lower levels of glutamic acid decarboxylase 67 (GAD67) mRNA and protein, which is responsible for most cortical GABA synthesis, are accompanied by lower levels of GABA membrane transporter 1 (GAT1) mRNA. These alterations are thought to be most prominent in the parvalbumin (PV)-containing subclass of interneurons, which also contain lower levels of PV mRNA. Since GAT1 and PV each reduce the availability of GABA at postsynaptic receptors, lower levels of GAT1 and PV mRNAs have been hypothesized to represent compensatory responses to an upstream reduction in cortical GABA synthesis in schizophrenia. However, such cause-and-effect hypotheses cannot be directly tested in a human illness. Consequently, we used two mouse models with reduced GAD67 expression specifically in PV neurons (PV(GAD67+/-)) or in all interneurons (GABA(GAD67+/-)) and quantified GAD67, GAT1 and PV mRNA levels using methods identical to those employed in studies of schizophrenia. Cortical levels of PV or GAT1 mRNAs were not altered in PV(GAD67+/-) mice during postnatal development or in adulthood. Furthermore, cellular analyses confirmed the predicted reduction in GAD67 mRNA, but failed to show a deficit in PV mRNA in these animals. Levels of PV and GAT1 mRNAs were also unaltered in GABA(GAD67+/-) mice. Thus, mouse lines with cortical reductions in GAD67 mRNA that match or exceed those present in schizophrenia, and that differ in the developmental timing and cell type-specificity of the GAD67 deficit, failed to provide proof-of-concept evidence that lower PV and GAT1 expression in schizophrenia are a consequence of lower GAD67 expression. Together, these findings suggest that the correlated decrements in cortical GAD67, PV and GAT1 mRNAs in schizophrenia may be a common consequence of some other upstream factor.
Assuntos
Córtex Cerebral/metabolismo , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Glutamato Descarboxilase/metabolismo , Parvalbuminas/metabolismo , Esquizofrenia/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Hibridização In Situ , Camundongos , Camundongos Mutantes , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Certain cognitive deficits in schizophrenia have been linked to dysfunction of prefrontal cortical (PFC) γ-aminobutyric acid (GABA) neurons and appear neurodevelopmental in nature. Since opioids suppress GABA neuron activity, we conducted the first study to determine 1) whether the µ opioid receptor (MOR), δ opioid receptor (DOR), and opioid ligand proenkephalin are altered in the PFC of a large cohort of schizophrenia subjects and 2) the postnatal developmental trajectory in monkey PFC of opioid markers that are altered in schizophrenia. We used quantitative polymerase chain reaction to measure mRNA levels from 42 schizophrenia and 42 matched healthy comparison subjects; 18 monkeys chronically exposed to haloperidol, olanzapine, or placebo; and 49 monkeys aged 1 week-11.5 years. We found higher levels for MOR mRNA (+27%) in schizophrenia but no differences in DOR or proenkephalin mRNAs. Elevated MOR mRNA levels in schizophrenia did not appear to be explained by substance abuse, psychotropic medications, or illness chronicity. Finally, MOR mRNA levels declined through early postnatal development, stabilized shortly before adolescence and increased across adulthood in monkey PFC. In schizophrenia, higher MOR mRNA levels may contribute to suppressed PFC GABA neuron activity and might be attributable to alterations in the postnatal developmental trajectory of MOR signaling.
Assuntos
Encefalinas/biossíntese , Córtex Pré-Frontal/metabolismo , Precursores de Proteínas/biossíntese , Receptores Opioides delta/biossíntese , Receptores Opioides mu/biossíntese , Esquizofrenia/metabolismo , Animais , Antipsicóticos/farmacologia , Benzodiazepinas/farmacologia , Feminino , Haloperidol/farmacologia , Humanos , Macaca fascicularis , Masculino , Pessoa de Meia-Idade , Olanzapina , Reação em Cadeia da Polimerase , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/crescimento & desenvolvimento , RNA Mensageiro/análise , Esquizofrenia/fisiopatologiaRESUMO
BACKGROUND: Cognitive disturbances in schizophrenia have been linked to a lower density of dendritic spines on pyramidal neurons in the prefrontal cortex (PFC). Complement component C4, which has previously been found at higher levels in schizophrenia, marks synapses for phagocytosis by microglia. Thus, elevated consumption of dendritic spines by microglia mediated through excessive complement activity may play a role in lower spine density in schizophrenia. However, it is unclear if microglia themselves have the molecular capacity for enhanced phagocytosis of spines in schizophrenia. METHODS: Transcript levels for complement components and microglia-specific phagocytic markers were quantified using quantitative PCR in the PFC of 62 matched pairs of schizophrenia and unaffected comparison subjects and in antipsychotic-exposed monkeys. RESULTS: Relative to comparison subjects, schizophrenia subjects had higher mRNA levels for C4 (+154 %); C1q (+69 %), which initiates the classical complement pathway that includes C4; and for microglia-specific markers that enable phagocytic activity including TAM receptor tyrosine kinases Axl (+27 %) and MerTK (+27 %) and lysosome-associated glycoprotein CD68 (+27 %) (all p ≤ .042). Transcript levels for microglial phagocytic markers were correlated with C4 mRNA levels in schizophrenia subjects (all r ≥ 0.31, p ≤ .015). We also found further evidence consistent with microglial activation in schizophrenia, including higher mRNA levels for THIK1 (TWIK-related halothane-inhibited potassium channel: +30 %) and lower mRNA levels for the purinergic receptor P2Y12 (-27 %) (all p ≤ .016). Transcript levels were unchanged in antipsychotic-exposed monkeys. CONCLUSIONS: These results are consistent with the presence of increased complement activity and an elevated molecular capacity of microglia for phagocytosis in the same schizophrenia subjects.
Assuntos
Antipsicóticos , Esquizofrenia , Animais , Esquizofrenia/tratamento farmacológico , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Microglia , Córtex Pré-Frontal/metabolismo , Fagocitose , RNA Mensageiro/metabolismo , HaplorrinosRESUMO
Bipolar disorder and schizophrenia have multiple clinical and genetic features in common, including shared risk associated with overlapping susceptibility loci in immune-related genes. Higher activity of the nuclear factor-κB (NF-κB) transcription factor complex, which regulates the transcription of multiple immune markers, has been reported to contribute to immune activation in the prefrontal cortex in schizophrenia. These findings suggest the hypothesis that elevated NF-κB activity is present in the prefrontal cortex in bipolar disorder in a manner similar to that seen in schizophrenia. Therefore, we quantified levels of NF-κB-related mRNAs in the prefrontal cortex of 35 matched pairs of bipolar disorder and unaffected comparison subjects using quantitative PCR. We found that transcript levels were higher in the prefrontal cortex of bipolar disorder subjects for several NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs, and were lower for an NF-κB inhibitor. Transcript levels for NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs levels were also highly correlated with each other. This pattern of elevated transcript levels for NF-κB-related markers in bipolar disorder is similar to that previously reported in schizophrenia, suggesting that cortical immune activation is a shared pathophysiological feature between the two disorders.
Assuntos
Transtorno Bipolar , Esquizofrenia , Transtorno Bipolar/genética , Humanos , NF-kappa B/metabolismo , Córtex Pré-Frontal/metabolismo , RNA Mensageiro , Esquizofrenia/genéticaRESUMO
BACKGROUND: Transcript levels for cytokines and the viral restriction factor interferon-induced transmembrane protein are markedly higher in the prefrontal cortex in schizophrenia. These gene products are regulated by the nuclear factor-κB (NF-κB) transcriptional complex. NF-κB activity, which requires the formation of NF-κB family member heterodimers, is regulated by activation receptors, kinases, and inhibitors. Whether any of these factors are altered in schizophrenia is not known. It is also unclear whether NF-κB-related disturbances reflect ongoing cortical immune activation or a long-lasting response to a prenatal immune-related insult. METHODS: Transcript levels for NF-κB pathway markers were assessed using quantitative polymerase chain reaction in the prefrontal cortex from 1) 62 matched pairs of schizophrenia and unaffected comparison subjects, 2) antipsychotic-exposed monkeys, and 3) adult mice exposed prenatally to maternal immune activation or in adulthood to the immune stimulant polyinosinic-polycytidylic acid. RESULTS: In schizophrenia subjects, but not antipsychotic-exposed monkeys, we found higher messenger RNA levels for 1) most NF-κB family members, 2) all NF-κB activation receptors, 3) several kinases, and 4) one inhibitor (IκBα) whose transcript level is itself regulated by NF-κB activity. A similar pattern of elevated NF-κB-related messenger RNA levels was seen in adult mice that received daily polyinosinic-polycytidylic acid injections, but not in adult mice subjected to maternal immune activation in utero. CONCLUSIONS: Higher NF-κB activity, evidenced by elevated transcript levels for NF-κB family members, activation receptors, and kinases, may contribute to increased markers of cortical immune activation in schizophrenia.
Assuntos
Citocinas/sangue , NF-kappa B/sangue , Esquizofrenia/metabolismo , Adulto , Animais , Antipsicóticos/uso terapêutico , Estudos de Casos e Controles , Feminino , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Córtex Pré-Frontal/imunologia , Gravidez , RNA Mensageiro/sangue , Esquizofrenia/tratamento farmacológico , Transdução de SinaisRESUMO
Altered cannabinoid 1 receptor (CB1R) expression has been reported in the brain of subjects with schizophrenia, a developmental mental illness that usually emerges in late adolescence/early adulthood. However, the developmental period at which changes in the CB1R expression appear in schizophrenia is unknown. To gain insight into this factor, we assessed the postnatal developmental trajectory of CB1R expression in the methylazoxymethanol (MAM) model of schizophrenia. Using in situ hybridization with film and grain analyses, CB1R messenger RNA (mRNA) levels were quantified in multiple brain regions, including the medial prefrontal cortex (mPFC), secondary motor cortex, dorsomedial and dorsolateral striatum, dorsal subregions and ventral subiculum of the hippocampus, of MAM-treated rats and normal controls at three developmental periods [juvenile - postnatal day (PD) 30; adolescence - PD45; and adulthood - PD85]. In all brain regions studied, CB1R mRNA levels were highest in juveniles and then decreased progressively toward adolescent and adult levels in control and MAM-treated rats. However, in MAM-treated rats, CB1R mRNA levels were lower in the mPFC at PD85 and higher in the dorsolateral striatum at PD45 and PD85 relative to controls. Cellular analyses confirmed the changes in CB1R mRNA expression in MAM-treated rats. These findings are in accordance with previous studies showing a decrease in the CB1R mRNA expression from juvenile period to adolescence to adulthood in cortical, striatal, and hippocampal regions. Additionally, similar to most of the schizophrenia-like signs observed in the MAM model, embryonic exposure to MAM leads to schizophrenia-related changes in CB1R mRNA expression that only emerge later in development.
Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , RNA Mensageiro/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Esquizofrenia/metabolismo , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Hibridização In Situ , Masculino , Acetato de Metilazoximetanol/análogos & derivados , Distribuição Aleatória , Ratos Sprague-DawleyRESUMO
OBJECTIVE: Lower dendritic spine density on layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) appears to contribute to cognitive dysfunction in schizophrenia, whereas psychosis is associated with excessive dopamine release in the striatum. These findings may be related via excitatory projections from the DLPFC to the ventral mesencephalon, the location of dopamine cells projecting to the striatum. Consistent with this hypothesis, deletion of the actin-related protein-2/3 (ARP2/3) complex, which regulates the actin cytoskeleton supporting dendritic spines, produced spine loss in cortical pyramidal cells and striatal hyperdopaminergia in mice. The authors sought to determine whether the ARP2/3 complex is altered in schizophrenia. METHOD: In matched pairs of schizophrenia and comparison subjects, transcript levels of ARP2/3 complex signaling pathway were assessed in laser-microdissected DLPFC layer 3 and 5 pyramidal cells and layer 3 parvalbumin interneurons, and in total DLPFC gray matter. RESULTS: Transcript levels of ARP2/3 complex subunits and of nucleation promotion factors that regulate the ARP2/3 complex were significantly lower in DLPFC layer 3 and 5 pyramidal cells in schizophrenia. In contrast, these transcripts were unaltered, or only modestly changed, in parvalbumin interneurons and DLPFC gray matter. CONCLUSIONS: Down-regulation of the ARP2/3 complex signaling pathway, a common final pathway for multiple signaling cascades that regulate the actin cytoskeleton, would compromise the structural stability of spines, leading to their loss. In concert with findings from deletion of the ARP2/3 complex in mice, these findings support the idea that spine deficits in the DLPFC may contribute to subcortical hyperdopaminergia in schizophrenia.
Assuntos
Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Regulação para Baixo/genética , Expressão Gênica/genética , Córtex Pré-Frontal/metabolismo , Células Piramidais/metabolismo , Esquizofrenia/genética , Transdução de Sinais/genética , Adulto , Animais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Esquizofrenia/diagnósticoRESUMO
Cannabis use has been reported to increase the risk of developing schizophrenia and to worsen symptoms of the illness. Both of these outcomes might be attributable to the disruption by cannabis of the endogenous cannabinoid system's spatiotemporal regulation of the inhibitory circuitry in the prefrontal cortex that is essential for core cognitive processes, such as working memory, which are impaired in schizophrenia. In the healthy brain, the endocannabinoid 2-arachidonylglycerol 1) is synthesized by diacylglycerol lipase in pyramidal neurons; 2) travels retrogradely to nearby inhibitory axon terminals that express the primary type 1 cannabinoid receptor (CB1R); 3) binds to CB1R, which inhibits gamma-aminobutyric acid release from the cholecystokinin-containing population of interneurons; and 4) is metabolized by either monoglyceride lipase, which is located in the inhibitory axon terminal, or by α-ß-hydrolase domain 6, which is co-localized presynaptically with diacylglycerol lipase. Investigations of the endogenous cannabinoid system in the prefrontal cortex of subjects with schizophrenia have found evidence of higher metabolism of 2-arachidonylglycerol, as well as both greater CB1R receptor binding and lower levels of CB1R messenger RNA and protein. Current views on the potential pathogenesis of these alterations, including disturbances in the development of the endogenous cannabinoid system, are discussed. In addition, how interactions between these alterations in the endocannabinoid system and those in other inhibitory neurons in the prefrontal cortex in subjects with schizophrenia might increase the liability to adverse outcomes with cannabis use is considered.
Assuntos
Ácidos Araquidônicos/efeitos adversos , Endocanabinoides/efeitos adversos , Glicerídeos/efeitos adversos , Interneurônios/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Células Piramidais/efeitos dos fármacos , Esquizofrenia/fisiopatologia , Ácidos Araquidônicos/farmacologia , Cognição , Endocanabinoides/farmacologia , Glicerídeos/farmacologia , Humanos , RNA Mensageiro/genética , Receptor CB1 de Canabinoide/genética , Transdução de Sinais , Ácido gama-Aminobutírico/metabolismoRESUMO
Altered inhibition from parvalbumin-containing GABA neurons is thought to contribute to impaired gamma frequency oscillations and cognitive deficits in schizophrenia. Crabtree and colleagues report that proline dehydrogenase deficits produce excessive cytosolic levels of the GABA-mimetic l-proline which impairs GABA synthesis and gamma oscillations in a manner that mimics schizophrenia.
Assuntos
Prolina , Esquizofrenia , Neurônios GABAérgicos , Parvalbuminas , Córtex Pré-Frontal , Ácido gama-AminobutíricoRESUMO
Dysfunction of prefrontal cortex (PFC) inhibitory neurons that express the calcium-binding protein parvalbumin or the neuropeptide somatostatin in schizophrenia may be related to disturbances in the migration, phenotypic specification, and/or maturation of these neurons. These pre- and postnatal developmental stages are regulated in a cell type-specific manner by various transcription factors and co-activators, fibroblast growth factor receptors (FgfR), and other molecular markers. Consequently, we used quantitative PCR to quantify mRNA levels for these developmental regulators in the PFC of 62 schizophrenia subjects in whom parvalbumin and somatostatin neuron disturbances were previously reported, and in antipsychotic-exposed monkeys. Relative to unaffected comparison subjects, subjects with schizophrenia exhibited elevated mRNA levels for 1) the transcription factor MafB, which is expressed by parvalbumin and somatostatin neurons as they migrate from the medial ganglionic eminence to the cortex, 2) the transcriptional coactivator PGC-1α, which is expressed postnatally by parvalbumin neurons to maintain parvalbumin levels and inhibitory function, and 3) FgfR1, which is required for the migration and phenotypic specification of parvalbumin and somatostatin neurons. Elevations in these markers were most prominent in younger schizophrenia subjects and were not present in antipsychotic-exposed monkeys. Finally, expression levels of other important developmental regulators (i.e. Dlx1, Dlx5, Dlx6, SATB1, Sip1/Zeb2, ST8SIA4, cMaf, Nkx6.2, and Arx) were not altered in schizophrenia. The over-expression of a subset of molecular markers with distinct roles in the pre- and postnatal development of parvalbumin and somatostatin neurons might reflect compensatory mechanisms to sustain the development of these neurons in the face of other insults.
Assuntos
Neurônios/metabolismo , Parvalbuminas/metabolismo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/metabolismo , Somatostatina/metabolismo , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Modelos Animais de Doenças , Feminino , Expressão Gênica , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Humanos , Macaca fascicularis , Fator de Transcrição MafB/metabolismo , Masculino , Pessoa de Meia-Idade , Neurônios/efeitos dos fármacos , Olanzapina , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Esquizofrenia/tratamento farmacológicoRESUMO
OBJECTIVE: Alternative splicing of ErbB4 transcripts is dysregulated in the dorsolateral prefrontal cortex in schizophrenia. ErbB4 regulates the activity of parvalbumin interneurons, and therefore dysregulated ErbB4 splicing could contribute to lower parvalbumin interneuron activity and consequently lower parvalbumin levels in schizophrenia. However, ErbB4 is also present in calretinin interneurons, which are not affected in schizophrenia. Therefore, the authors hypothesized that dysregulated ErbB4 splicing occurs selectively in parvalbumin interneurons and is associated with lower parvalbumin levels in schizophrenia. METHOD: Tissue samples enriched in calretinin and parvalbumin interneurons were laser microdissected from dorsolateral prefrontal cortex layers 2 and 4, respectively, from matched pairs of schizophrenia and comparison subjects. Transcript levels for pan-ErbB4, four ErbB4 splicing variants (JM-a, JM-b, CYT-1, CYT-2), parvalbumin, and calretinin were quantified by quantitative polymerase chain reaction (qPCR) in each layer. Transcript levels for myocardial infarction associated transcript (MIAT), which regulates ErbB4 splicing, were quantified in gray matter by qPCR and in parvalbumin interneurons by microarray. RESULTS: Calretinin and parvalbumin mRNAs were preferentially expressed in layers 2 and 4, respectively. In schizophrenia subjects, lower parvalbumin levels, higher CYT-1 and JM-a levels, and lower CYT-2 and JM-b levels were detected selectively in layer 4. In layer 4, the JM-a/JM-b ratio was inversely correlated with parvalbumin levels in schizophrenia subjects. MIAT levels were preferentially higher in parvalbumin interneurons in schizophrenia subjects. CONCLUSIONS: These findings suggest that elevated MIAT expression alters ErbB4 splicing selectively in parvalbumin interneurons in schizophrenia. Dysregulated ErbB4 splicing in schizophrenia may contribute to lower activity of parvalbumin interneurons and an activity-dependent down-regulation of parvalbumin expression.
Assuntos
Parvalbuminas/metabolismo , Córtex Pré-Frontal/metabolismo , Receptor ErbB-4/genética , Esquizofrenia , Adulto , Processamento Alternativo , Regulação para Baixo , Feminino , Humanos , Interneurônios/metabolismo , Masculino , Esquizofrenia/genética , Esquizofrenia/metabolismoRESUMO
N-methyl-d-aspartate receptor (NMDAR) hypofunction in the dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathology of schizophrenia. NMDAR activity is negatively regulated by some G protein-coupled receptors (GPCRs). Signaling through these GPCRs is reduced by Regulator of G protein Signaling 4 (RGS4). Thus, lower levels of RGS4 would enhance GPCR-mediated reductions in NMDAR activity and could contribute to NMDAR hypofunction in schizophrenia. In this study, we quantified RGS4 mRNA and protein levels at several levels of resolution in the DLPFC from subjects with schizophrenia and matched healthy comparison subjects. To investigate molecular mechanisms that could contribute to altered RGS4 levels, we quantified levels of small noncoding RNAs, known as microRNAs (miRs), which regulate RGS4 mRNA integrity after transcription. RGS4 mRNA and protein levels were significantly lower in schizophrenia subjects and were positively correlated across all subjects. The RGS4 mRNA deficit was present in pyramidal neurons of DLPFC layers 3 and 5 of the schizophrenia subjects. In contrast, levels of miR16 were significantly higher in the DLPFC of schizophrenia subjects, and higher miR16 levels predicted lower RGS4 mRNA levels. These findings provide convergent evidence of lower RGS4 mRNA and protein levels in schizophrenia that may result from increased expression of miR16. Given the role of RGS4 in regulating GPCRs, and consequently the strength of NMDAR signaling, these findings could contribute to the molecular substrate for NMDAR hypofunction in DLPFC pyramidal cells in schizophrenia.
Assuntos
MicroRNAs/metabolismo , Córtex Pré-Frontal/metabolismo , Transtornos Psicóticos/metabolismo , Proteínas RGS/metabolismo , Esquizofrenia/metabolismo , Transdução de Sinais/fisiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismoRESUMO
Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothesis, we evaluated the expression of mRNAs for PV, another calcium-binding protein, calretinin (CR), and glutamic acid decarboxylase (GAD67) in postmortem brain specimens from 15 pairs of subjects with schizophrenia and matched control subjects using single- and dual-label in situ hybridization. Signal intensity for PV mRNA expression in PFC area 9 was significantly decreased in the subjects with schizophrenia, predominantly in layers III and IV. Analysis at the cellular level revealed that this decrease was attributable principally to a reduction in PV mRNA expression per neuron rather than by a decreased density of PV mRNA-positive neurons. In contrast, the same measures of CR mRNA expression were not altered in schizophrenia. These findings were confirmed by findings from cDNA microarray studies using different probes. Across the subjects with schizophrenia, the decrease in neuronal PV mRNA expression was highly associated (r = 0.84) with the decrease in the density of neurons containing detectable levels of GAD67 mRNA. Furthermore, simultaneous detection of PV and GAD67 mRNAs revealed that in subjects with schizophrenia only 55% of PV mRNA-positive neurons had detectable levels of GAD67 mRNA. Given the critical role that PV-containing GABA neurons appear to play in regulating the cognitive functions mediated by the PFC, the selective alterations in gene expression in these neurons may contribute to the cognitive deficits characteristic of schizophrenia.
Assuntos
Benzotropina/análogos & derivados , Perfilação da Expressão Gênica , Haloperidol/análogos & derivados , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Ácido gama-Aminobutírico/biossíntese , Adulto , Idoso , Animais , Autorradiografia , Benzotropina/farmacologia , Calbindina 2 , Contagem de Células , Feminino , Glutamato Descarboxilase/genética , Haloperidol/farmacologia , Humanos , Hibridização In Situ , Isoenzimas/genética , Macaca fascicularis , Masculino , Pessoa de Meia-Idade , Inibição Neural , Neurônios/classificação , Neurônios/efeitos dos fármacos , Neurônios/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Parvalbuminas/genética , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , Proteína G de Ligação ao Cálcio S100/genética , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Especificidade por Substrato , Transmissão Sináptica , TempoRESUMO
Alterations in inhibitory (GABA) neurons, including deficiencies in the GABA synthesizing enzyme GAD67, in the prefrontal cortex in schizophrenia are pronounced in the subpopulations of neurons that contain the calcium-binding protein parvalbumin or the neuropeptide somatostatin. The presence of similar illness-related deficits in the transcription factor Lhx6, which regulates prenatal development of parvalbumin and somatostatin neurons, suggests that cortical GABA neuron dysfunction may be related to disturbances in utero. Since the chemokine receptors CXCR4 and CXCR7 guide the migration of cortical parvalbumin and somatostatin neurons from their birthplace in the medial ganglionic eminence to their final destination in the neocortex, we sought to determine whether altered CXCR4 and/or CXCR7 mRNA levels were associated with disturbances in GABA-related markers in schizophrenia. Quantitative PCR was used to quantify CXCR4 and CXCR7 mRNA levels in the prefrontal cortex of 62 schizophrenia and 62 healthy comparison subjects that were previously characterized for markers of parvalbumin and somatostatin neurons and in antipsychotic-exposed monkeys. We found elevated mRNA levels for CXCR7 (+29%; p<.0001) and CXCR4 (+14%, p=.052) in schizophrenia subjects but not in antipsychotic-exposed monkeys. CXCR7 mRNA levels were inversely correlated with mRNA levels for GAD67, parvalbumin, somatostatin, and Lhx6 in schizophrenia but not in healthy subjects. These findings suggest that higher mRNA levels for CXCR7, and possibly CXCR4, may represent a compensatory mechanism to sustain the migration and correct positioning of cortical parvalbumin and somatostatin neurons in the face of other insults that disrupt the prenatal development of cortical GABA neurons in schizophrenia.
Assuntos
Interneurônios/patologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia , Adulto , Análise de Variância , Feminino , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Humanos , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Parvalbuminas/genética , Parvalbuminas/metabolismo , RNA Mensageiro/metabolismo , Receptores CXCR/genética , Receptores CXCR/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Somatostatina/genética , Somatostatina/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
OBJECTIVE: Immune-related abnormalities are commonly reported in schizophrenia, including higher mRNA levels for the viral restriction factor interferon-induced transmembrane protein (IFITM) in the prefrontal cortex. The authors sought to clarify whether higher IFITM mRNA levels and other immune-related disturbances in the prefrontal cortex are the consequence of an ongoing molecular cascade contributing to immune activation or the reflection of a long-lasting maladaptive response to an in utero immune-related insult. METHOD: Quantitative polymerase chain reaction was employed to measure mRNA levels for immune-related cytokines and transcriptional regulators, including those reported to regulate IFITM expression, in the prefrontal cortex from 62 schizophrenia and 62 healthy subjects and from adult mice exposed prenatally to maternal immune activation or in adulthood to the immune stimulant poly(I:C). RESULTS: Schizophrenia subjects had markedly higher mRNA levels for interleukin 6 (IL-6) (+379%) and interferon-ß (+29%), which induce IFITM expression; lower mRNA levels for Schnurri-2 (-10%), a transcriptional inhibitor that lowers IFITM expression; and higher mRNA levels for nuclear factor-κB (+86%), a critical transcription factor that mediates cytokine regulation of immune-related gene expression. In adult mice that received daily poly(I:C) injections, but not in offspring with prenatal exposure to maternal immune activation, frontal cortex mRNA levels were also markedly elevated for IFITM (+304%), multiple cytokines including IL-6 (+493%), and nuclear factor-κB (+151%). CONCLUSIONS: These data suggest that higher prefrontal cortex IFITM mRNA levels in schizophrenia may be attributable to adult, but not prenatal, activation of multiple immune markers and encourage further investigation into the potential role of these and other immune markers as therapeutic targets in schizophrenia.
Assuntos
Córtex Pré-Frontal/imunologia , RNA Mensageiro/imunologia , Esquizofrenia/imunologia , Adulto , Animais , Antígenos de Diferenciação/efeitos dos fármacos , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Estudos de Casos e Controles , Córtex Cerebral/imunologia , Córtex Cerebral/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Indutores de Interferon/farmacologia , Interferon beta/efeitos dos fármacos , Interferon beta/genética , Interferon beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Pessoa de Meia-Idade , NF-kappa B/efeitos dos fármacos , NF-kappa B/genética , NF-kappa B/imunologia , Poli I-C/farmacologia , Córtex Pré-Frontal/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/efeitos dos fármacos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Esquizofrenia/genética , Fatores de Transcrição/genética , Fatores de Transcrição/imunologiaRESUMO
BACKGROUND: Schizophrenia is a neurodevelopmental disorder with altered expression of GABA-related genes in the prefrontal cortex (PFC). However, whether these gene expression abnormalities reflect disturbances in postnatal developmental processes before clinical onset or arise as a consequence of clinical illness remains unclear. METHODS: Expression levels for 7 GABA-related transcripts (vesicular GABA transporter [vGAT], GABA membrane transporter [GAT1], GABAA receptor subunit α1 [GABRA1] [novel in human and monkey cohorts], glutamic acid decarboxylase 67 [GAD67], parvalbumin, calretinin, and somatostatin [previously reported in human cohort, but not in monkey cohort]) were quantified in the PFC from 42 matched pairs of schizophrenia and comparison subjects and from 49 rhesus monkeys ranging in age from 1 week postnatal to adulthood. RESULTS: Levels of vGAT and GABRA1, but not of GAT1, messenger RNAs (mRNAs) were lower in the PFC of the schizophrenia subjects. As previously reported, levels of GAD67, parvalbumin, and somatostatin, but not of calretinin, mRNAs were also lower in these subjects. Neither illness duration nor age accounted for the levels of the transcripts with altered expression in schizophrenia. In monkey PFC, developmental changes in expression levels of many of these transcripts were in the opposite direction of the changes observed in schizophrenia. For example, mRNA levels for vGAT, GABRA1, GAD67, and parvalbumin all increased with age. CONCLUSIONS: Together with published reports, these findings support the interpretation that the altered expression of GABA-related transcripts in schizophrenia reflects a blunting of normal postnatal development changes, but they cannot exclude a decline during the early stages of clinical illness.
Assuntos
Córtex Pré-Frontal/metabolismo , Transtornos Psicóticos/genética , RNA Mensageiro/metabolismo , Esquizofrenia/genética , Ácido gama-Aminobutírico/metabolismo , Adulto , Animais , Calbindina 2/genética , Estudos de Casos e Controles , Progressão da Doença , Feminino , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Glutamato Descarboxilase/genética , Humanos , Macaca mulatta , Masculino , Pessoa de Meia-Idade , Parvalbuminas/genética , Córtex Pré-Frontal/crescimento & desenvolvimento , Transtornos Psicóticos/metabolismo , Receptores de GABA-A/genética , Esquizofrenia/metabolismo , Somatostatina/genética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genéticaRESUMO
BACKGROUND: Schizophrenia is associated with both reductions in prefrontal cortical (PFC) inhibitory markers and in neuron number in the mediodorsal thalamus (MDTN), which provides excitatory input to the PFC. To investigate the potential pathophysiologic relationship between these observations, we sought to provide experimental evidence that a reduction in MDTN neurons can produce decreased PFC glutamate decarboxylase (GAD(67)) mRNA expression. METHODS: Ibotenic acid was injected bilaterally into MDTN in rats. Four weeks later, thalamic lesion volumes were assessed stereologically, and PFC GAD(67) mRNA expression was measured using in situ hybridization. RESULTS: Selective MDTN lesions produced no changes in PFC GAD(67) mRNA expression, either overall or by cortical layer, and lesion volumes and GAD(67) mRNA expression were not correlated. CONCLUSIONS: In rats, a substantial lesion of MDTN neurons does not decrease PFC GAD(67) mRNA expression. These results do not support the hypothesis that decreased PFC GAD(67) mRNA expression in schizophrenia is attributable to a reduction in MDTN neuron number.
Assuntos
Inibição Neural/fisiologia , Vias Neurais/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/fisiopatologia , Tálamo/patologia , Animais , Modelos Animais de Doenças , Agonistas de Aminoácidos Excitatórios/toxicidade , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Ácido Ibotênico/toxicidade , Hibridização In Situ/métodos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Córtex Motor/metabolismo , Vias Neurais/metabolismo , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Tálamo/fisiopatologiaRESUMO
RATIONALE: Disturbances in critical cognitive processes, such as working memory, are now regarded as core features of schizophrenia, but available pharmacological treatments produce little or no improvement in these cognitive deficits. Although other explanations are possible, these cognitive deficits appear to reflect a disturbance in executive control, the processes that facilitate complex information processing and behavior and that include context representation and maintenance, functions dependent on the dorsolateral prefrontal cortex (DLPFC). Studies in non-human primates indicate that normal working memory function depends upon appropriate GABA neurotransmission in the DLPFC, and alterations in markers of GABA neurotransmission are well documented in the DLPFC of subjects with schizophrenia. OBJECTIVES: Thus, the purpose of this paper is to review the nature of the altered GABA neurotransmission in the DLPFC in schizophrenia, and to consider how these findings might inform the search for new treatments for cognitive dysfunction in this illness. RESULTS AND CONCLUSIONS: Postmortem studies suggest that markers of reduced GABA neurotransmission in schizophrenia may be selective for, or at least particularly prominent in, the subclass of GABA neurons, chandelier cells, that provide inhibitory input to the axon initial segment of populations of pyramidal neurons. Given the critical role that chandelier cells play in synchronizing the activity of pyramidal neurons, the pharmacological amelioration of this deficit may be particularly effective in normalizing the neural network activity required for working memory function. Because GABA(A) receptors containing the a(2) subunit are selectively localized to the axon initial segment of pyramidal cells, and appear to be markedly up-regulated in schizophrenia, treatment with novel benzodiazepine-like agents with selective activity at GABA(A) receptors containing the a(2) subunit may be effective adjuvant agents for improving working memory function in schizophrenia.
Assuntos
GABAérgicos/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Córtex Pré-Frontal/metabolismo , Esquizofrenia/complicações , Ácido gama-Aminobutírico/metabolismo , Animais , Proteínas da Membrana Plasmática de Transporte de GABA , Glutamato Descarboxilase/metabolismo , Humanos , Imuno-Histoquímica/métodos , Isoenzimas/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Transtornos da Memória/etiologia , Memória de Curto Prazo/efeitos dos fármacos , Modelos Neurológicos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Parvalbuminas/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de GABA/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
In schizophrenia, critical deficits in cognitive functions appear to reflect altered neural processing in the prefrontal cortex (PFC). Given the essential role of inhibitory neurotransmission in mediating these cognitive functions, we sought to determine whether abnormalities in the inhibitory circuitry of the PFC may contribute to the cognitive deficits of schizophrenia. In situ hybridization analyses in postmortem brain tissue from subjects with schizophrenia revealed that a subset of GABA neurons in PFC layers 1-5 do not express detectable levels of the mRNAs encoding glutamate decarboxylase (GAD(67)), a synthesizing enzyme for GABA, or the GABA membrane transporter (GAT-1), which is responsible for the reuptake of GABA into the nerve terminal. Furthermore, the affected GABA neurons appear to include chandelier cells, since decreased expression of GAT-1 mRNA is associated with decreased GAT-1 protein immunoreactivity in chandelier neuron axon terminals. Finally, immunocytochemical studies revealed that decreased GAT-1 immunoreactivity in chandelier neuron axon terminals is associated with an increase in a marker of GABA(A) receptors at the postsynaptic targets of chandelier neuron axons, the axon initial segment (AIS) of pyramidal neurons. These findings suggest that schizophrenia is associated with an up-regulation of GABA(A) receptors at pyramidal neuron AIS in response to deficient GABAergic input from chandelier neurons. Selective disruptions in inhibitory neurotransmission are likely to distort aspects of pyramidal neuron function important for working memory tasks, and thus may contribute to cognitive dysfunction in schizophrenia.