RESUMO
We tested the hypothesis that, compared with subjects with no history of psychiatric illness (controls), changes in gene expression in the dorsolateral prefrontal cortex from two subgroups of subjects with schizophrenia, one with a marked deficit in muscarinic M1 receptors (muscarinic receptor-deficit schizophrenia (MRDS)), would identify different biochemical pathways that would be affected by their aetiologies. Hence, we measured levels of cortical (Brodmann area 9) mRNA in 15 MRDS subjects, 15 subjects with schizophrenia but without a deficit in muscarinic M1 receptors (non-MRDS) and 15 controls using Affymetrix Exon 1.0 ST arrays. Levels of mRNA for 65 genes were significantly different in the cortex of subjects with MRDS and predicted changes in pathways involved in cellular movement and cell-to-cell signalling. Levels of mRNA for 45 genes were significantly different in non-MRDS and predicted changes in pathways involved in cellular growth and proliferation as well as cellular function and maintenance. Changes in gene expression also predicted effects on pathways involved in amino acid metabolism, molecular transport and small-molecule biochemistry in both MRDS and non-MRDS. Overall, our data argue a prominent role for glial function in MRDS and neurodevelopment in non-MRDS. Finally, the interactions of gene with altered levels of mRNA in the cortex of subjects with MRDS suggest many of their affects will be upstream of the muscarinic M1 receptor. Our study gives new insight into the molecular pathways affected in the cortex of subjects with MRDS and supports the notion that studying subgroups within the syndrome of schizophrenia is worthwhile.
Assuntos
Receptor Muscarínico M1/genética , Esquizofrenia/genética , Encéfalo/patologia , Córtex Cerebral/metabolismo , Feminino , Previsões , Humanos , Masculino , Neuroglia/patologia , Córtex Pré-Frontal , RNA Mensageiro/metabolismo , Transcriptoma/genéticaRESUMO
Our previous study demonstrated that phospholipase C beta 1 mRNA was down-regulated in Brodmann's area 46 from subjects with schizophrenia. However, phospholipase C beta 1 protein has also been shown to be lower in Brodmann's area 8 and 9 from teenage suicide subjects, creating a potential confound in interpreting the findings in schizophrenia due to the high suicide rate associated with this disorder. To begin to reconcile and consolidate these findings, in this study, we measured mRNA and protein levels of phospholipase C beta 1 variants a and b in Brodmann's area 46 and Brodmann's area 9 from subjects with schizophrenia, many of whom were suicide completers, and determined the diagnostic specificity of observed findings. Consistent with our previous study, levels of phospholipase C beta 1 a and b mRNA, but not protein, were lower in Brodmann's area 46 from subjects with schizophrenia. In Brodmann's area 9, phospholipase C beta 1a protein levels were lower in subjects with schizophrenia, while phospholipase C beta 1b mRNA was higher and protein was lower in those that had died of suicide. Altered protein levels in Brodmann's area 9 appeared to be diagnostically specific, as we did not detect these changes in subjects with bipolar disorder, major depressive disorder or suicide completers with no diagnosis of mental illness. We further assessed the relationship between phospholipase C beta 1 and levels of muscarinic receptors (CHRMs) that signal through this protein, in both human and Chrm knockout mouse central nervous system tissue, and found no strong relationship between the two. Understanding central nervous system differences in downstream effector pathways in schizophrenia may lead to improved treatment strategies and help to identify those at risk of suicide.
RESUMO
Studies using central nervous system tissue obtained postmortem suggest pathways involved in energy and metabolism contribute to the pathophysiology of schizophrenia; neuroimaging studies suggesting glucose metabolism is particularly affected in the striatum. To gain information on the status of pathways involved in glucose metabolism in the striatum, we measured levels of glucose, pyruvate, acetyl-CoA and lactate as well as the ß subunit of pyruvate dehydrogenase, a rate limiting enzyme, in the postmortem tissue from subjects with schizophrenia and age/sex-matched controls. The subjects with schizophrenia were made up of two subgroups, which could be divided because they either had (muscarinic receptor deficit schizophrenia (MRDS)), or did not have (non-MRDS), a marked deficit in cortical muscarinic receptors. Compared to controls, levels of ß subunit of pyruvate dehydrogenase were lower (Δ mean=-20%) and levels of pyruvate (Δ mean=+47%) and lactate (Δ mean=+15%) were significantly higher in the striatum from subjects with schizophrenia. Notably, in subjects with non-MRDS, striatal levels of ß subunit of pyruvate dehydrogenase were lower (Δ mean=-29%), whereas levels of pyruvate (Δ mean=-66%), acetyl-CoA (Δ mean=-28%) and glucose (Δ mean=-27%) were higher, whereas levels of lactate (Δ mean=+17%) were higher in MRDS. Finally, discriminate analyses using levels the ß subunit of pyruvate dehydrogenase and glucose, or better still, ß subunit of pyruvate dehydrogenase and glucose in combination with pyruvate, lactate or acetyl-CoA could separate subjects with non-MRDS from controls with high levels of specificity (up to 93%) and selectivity (up to 91%). Our data show the benefit of being able to study defined subgroups within the syndrome of schizophrenia as such an approach has revealed that changes in glucose metabolism may be a significant contributor to the pathophysiology of non-MRDS.
Assuntos
Glicemia/metabolismo , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Metabolismo Energético/fisiologia , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Acetilcoenzima A/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , História do Século XVI , História do Século XVII , Humanos , Ácido Láctico/metabolismo , Masculino , Pessoa de Meia-Idade , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Piruvato Desidrogenase (Lipoamida)/metabolismo , Ácido Pirúvico/metabolismo , Receptores Muscarínicos/fisiologia , Valores de Referência , Esquizofrenia/classificaçãoRESUMO
Based on our previous finding of a seven-miRNA (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) signature as a potential biomarker for schizophrenia, this study aimed to examine if hospitalization could affect expressions of these miRNAs. We compared their expression levels between acute state and partial remission state in people with schizophrenia (n=48) using quantitative PCR method. Further, to examine whether the blood and brain show similar expression patterns, the expressions of two miRNAs (hsa-miR-34a and hsa-miR-548d) were examined in the postmortem brain tissue of people with schizophrenia (n=25) and controls (n=27). The expression level of the seven miRNAs did not alter after ~2 months of hospitalization with significant improvement in clinical symptoms, suggesting the miRNAs could be traits rather than state-dependent markers. The aberrant expression seen in the blood of hsa-miR-34a and hsa-miR-548d were not present in the brain samples, but this does not discount the possibility that the peripheral miRNAs could be clinically useful biomarkers for schizophrenia. Unexpectedly, we found an age-dependent increase in hsa-miR-34a expressions in human cortical (Brodmann area 46 (BA46)) but not subcortical region (caudate putamen). The correlation between hsa-miR-34a expression level in BA46 and age was much stronger in the controls than in the cases, and the corresponding correlation in the blood was only seen in the cases. The association between the miRNA dysregulations, the disease predisposition and aging warrants further investigation. Taken together, this study provides further insight on the candidate peripheral miRNAs as stable biomarkers for the diagnostics of schizophrenia.
Assuntos
Encéfalo/metabolismo , MicroRNAs/metabolismo , Esquizofrenia/metabolismo , Doença Aguda , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Indução de Remissão , Esquizofrenia/sangue , Adulto JovemRESUMO
Selenium binding protein 1 (SELENBP1) messenger RNA (mRNA) has previously been shown to be upregulated in the brain and blood from subjects with schizophrenia. We aimed to validate these findings in a new cohort using real-time PCR in Brodmann's Area (BA) 9, and to determine the disease specificity of increased SELENBP1 expression by measuring SELENBP1 mRNA in subjects with major depressive disorder and bipolar disorder. We then extended the study to include other cortical regions such as BA8 and BA44. SELENBP1 mRNA was higher in BA9 (P = 0.001), BA8 (P = 0.003) and BA44 (P = 0.0007) from subjects with schizophrenia. Conversely, in affective disorders, there was no significant difference in SELENBP1 mRNA in BA9 (P = 0.67), suggesting that the upregulation may be diagnosis specific. Measurement of SELENBP1 protein levels showed that changes in mRNA did not translate to changes in protein. In addition, chronic treatment of rats with antipsychotics did not significantly affect the expression of Selenbp1 in the cortex (P = 0.24). Our data show that elevated SELENBP1 transcript expression is widespread throughout the prefrontal cortex in schizophrenia, and confirm that this change is a consistent feature of schizophrenia and not a simple drug effect.
Assuntos
Córtex Pré-Frontal/metabolismo , Esquizofrenia/metabolismo , Proteínas de Ligação a Selênio/análise , Animais , Antipsicóticos/farmacologia , Transtorno Bipolar/metabolismo , Estudos de Casos e Controles , Clorpromazina/farmacologia , Transtorno Depressivo Maior/metabolismo , Feminino , Haloperidol/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/química , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Proteínas de Ligação a Selênio/biossíntese , Tioridazina/farmacologiaRESUMO
A considerable body of data supports a role for the central cholinergic system in the aetiologies of schizophrenia and mood disorders. There have been breakthroughs in gaining structural data on muscarinic receptors (CHRMs), understanding their role in CNS functioning and in synthesising drugs that can specifically target each of the 5 CHRMs. This means it is opportune to consider the role of specific CHRMs in the pathophysiologies of schizophrenia and mood disorders. This review will focus on data suggesting changes in levels of CHRM1 and CHRM4 implicate these receptors in the pathophysiology of schizophrenia whereas data suggest a role for CHRM2 in mood disorders. There will be a selected reference to recent developments in understanding the roles of CHRM1, 2 and 4 in CNS function and how these predict mechanisms by which these receptors could induce the symptoms prevalent in schizophrenia and mood disorders. Finally, there will be comments on the potential advantages and problems in targeting CHRM1 and CHRM4 to treat the symptoms of schizophrenia and CHRM2 to treat the symptom of depression.
Assuntos
Depressão/metabolismo , Transtornos do Humor/metabolismo , Receptores Muscarínicos/fisiologia , Esquizofrenia/metabolismo , Animais , Encéfalo/metabolismo , Depressão/patologia , Humanos , Transtornos do Humor/patologia , Esquizofrenia/patologia , Transmissão SinápticaRESUMO
Autophagy is a process preserving the balance between synthesis, degradation and recycling of cellular components and is therefore essential for neuronal survival and function. Several key proteins govern the autophagy pathway including beclin1 and microtubule associated protein 1 light chain 3 (LC3). Here, we show a brain-specific reduction in beclin1 expression in postmortem hippocampus of schizophrenia patients, not detected in peripheral lymphocytes. This is in contrast with activity-dependent neuroprotective protein (ADNP) and ADNP2, which we have previously found to be deregulated in postmortem hippocampal samples from schizophrenia patients, but that now showed a significantly increased expression in lymphocytes from related patients, similar to increases in the anti-apoptotic, beclin1-interacting, Bcl2. The increase in ADNP was associated with the initial stages of the disease, possibly reflecting a compensatory effect. The increase in ADNP2 might be a consequence of neuroleptic treatment, as seen in rats subjected to clozapine treatment. ADNP haploinsufficiency in mice, which results in age-related neuronal death, cognitive and social dysfunction, exhibited reduced hippocampal beclin1 and increased Bcl2 expression (mimicking schizophrenia and normal human aging). At the protein level, ADNP co-immunoprecipitated with LC3B suggesting a direct association with the autophagy process and paving the path to novel targets for drug design.
Assuntos
Autofagia/ética , Hipocampo/metabolismo , Hipocampo/patologia , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antipsicóticos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/genética , Autofagia/fisiologia , Proteína Beclina-1 , Estudos de Casos e Controles , Linhagem Celular Transformada , Clozapina/farmacologia , Feminino , Proteínas de Homeodomínio/genética , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Neuroblastoma/patologia , Ratos , Ratos Sprague-Dawley , Adulto Jovem , Proteína de Morte Celular Associada a bcl/genética , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
Many studies have shown decreased cortical muscarinic M1 receptors (CHRM1) in schizophrenia (Sz), with one study showing Sz can be separated into two populations based on a marked loss of CHRM1 (-75%) in -25% of people (Def-Sz) with the disorder. To better understand the mechanism contributing to the loss of CHRM1 in Def-Sz, we measured specific markers of gene expression in the cortex of people with Sz as a whole, people differentiated into Def-Sz and people with Sz that do not have a deficit in cortical CHRM1 (Non-Def-Sz) and health controls. We now report that cortical CHRM1 gene promoter methylation and CHRM1 mRNA are decrease in Sz, Def-Sz and Non-Def-Sz but levels of the micro RNA (miR)-107, a CHRM1 targeting miR, are increased only in Def-Sz. We also report in vitro data strongly supporting the notion that miR-107 levels regulate CHRM1 expression. These data suggest there is a reversal of the expected inverse relationship between gene promoter methylation and CHRM1 mRNA in people with Sz and that a breakdown in gene promoter methylation control of CHRM1 expression is contributing to the global pathophysiology of the syndrome. In addition, our data argues that increased levels of at least one miR, miR-107, is contributing to the marked loss of cortical CHRM1 in Def-Sz and this may be a differentiating pathophysiology. These latter data continue to support the hypothesis that microRNAs (miRNA) have a role in the underlying neurobiology of Sz but argue they are differentially affected in subsets of people within that syndrome.
Assuntos
Córtex Cerebral/metabolismo , Metilação de DNA/genética , Marcação de Genes/psicologia , MicroRNAs/genética , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Receptores Muscarínicos/genética , Esquizofrenia/genética , Adulto , Córtex Cerebral/patologia , Estudos de Coortes , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Receptor Muscarínico M1 , Receptores Muscarínicos/deficiência , Esquizofrenia/classificação , Esquizofrenia/patologiaRESUMO
The growing body of evidence implicating tumor necrosis factor-α (TNFα) in the pathophysiology of psychiatric disorders led us to measure levels of that protein in the cortex of subjects with major depressive disorders (MDD). Having reported an increase (458%) in the levels of the transmembrane (tmTNFα), but not the soluble (sTNFα), form of the protein in Brodmann's area (BA) 46, but not 24, in people with the disorder, we decided to examine additional components of TNFα-related pathways in the same regions in people with MDD and extend our studies to the same cortical regions of people with schizophrenia (Sz) and bipolar disorders (BD). Using postmortem tissue, western blots and quantitative PCR, we have now shown there is a significant increase (305%) in tmTNFα in Brodmann's area 24, but not 46, from subjects with BD, and that levels of the protein were not altered in Sz. Levels of sTNFα were not altered in BD or Sz. In addition, we have shown that levels of TNF receptor 1 (TNFR1) mRNA are increased in BA 24 (53%) and BA 46 (82%) in people with Sz, whereas levels of TNFR2 mRNA was decreased in BA 46 in people with mood disorders (MDD=-51%; BD=-67%). Levels of proteins frequently used as surrogate markers of neuronal, astrocytic and microglia numbers, as well as levels of the pro-inflammatory marker (interleukin 1ß), were not changed in the cortex of people with mood disorders. Our data suggest there are differential changes in TNFα-related markers in the cortex of people with MDD, BD and Sz that may not be related to classical inflammation and may cause changes in different TNFα-related signaling pathways.
Assuntos
Transtorno Bipolar/metabolismo , Córtex Cerebral/metabolismo , Transtorno Depressivo Maior/metabolismo , Esquizofrenia/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Interleucina-1beta/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/metabolismoRESUMO
Cognitive deficits in patients with schizophrenia are the biggest obstacle to achieving an independent and productive lifestyle, with these deficits being refractory to current drug treatments. Significantly, both nicotinic and muscarinic receptors (cholinoceptors) have been shown to have an important role in cognition and are therefore viewed as potential therapeutic targets for drugs designed to lessen cognitive deficits. Importantly, the demonstration that acetylcholinesterase inhibitors, which result in higher synaptic levels of acetylcholine, can reduce the cognitive deficits of schizophrenia suggested that under-stimulation of cholinoceptors could be associated with the cognitive deficits associated with this disorder. This has lead to a focus on the development of receptor agonists, partial agonists and allosteric agonists that can be used to stimulate cholinergic pathways and thus reduce the cognitive deficits of schizophrenia. In addition, muscarinic receptors have now been associated with the modulation of dopamine and may constitute an alternative target for the treatment of psychoses. Given these exciting new therapeutic initiatives, this review will outline current evidence that involves the cholinoceptors in the pathophysiology of schizophrenia and how these data can inform on approaches to more targeted treatments for the disorder.
Assuntos
Acetilcolina/metabolismo , Encéfalo/efeitos dos fármacos , Agonistas Colinérgicos/farmacologia , Fibras Colinérgicas/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Agonistas Colinérgicos/uso terapêutico , Fibras Colinérgicas/metabolismo , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Desenho de Fármacos , Humanos , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/genética , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Esquizofrenia/complicações , Esquizofrenia/metabolismo , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/fisiologiaRESUMO
The concept that acetylcholine is involved in the pathophysiologies of psychiatric disorders has existed since the 1950s. There is very strong evidence implicating a dysfunctional muscarinic system in schizophrenia, +with less information available for bipolar disorder and major depressive disorder. The translation of this evidence into clinically viable treatments has been disappointing; hampered by problems associated with developing drugs that target the requisite members of the muscarinic family, rather than all of the receptors, which results in unacceptable side-effect profiles. The discovery of additional binding sites, other than the one occupied by acetylcholine, has revitalised research into this aspect of psychopharmacology. New compounds are now being developed that have the potential to selectively target individual muscarinic receptors in the central nervous system. The question that remains to be answered is whether stimulating central muscarinic receptors will result in the reestablishment of normal central muscarinic activity? The purpose of this review is to (i) summarise the data supporting a role of the muscarinic system in schizophrenia, bipolar disorder and major depressive disorder, and (ii) give an overview of some of the new selective muscarinic ligands that are currently in development and try to address the issue of re-establishing appropriate central muscarinic function.
Assuntos
Transtornos Mentais/metabolismo , Receptores Muscarínicos/metabolismo , Acetilcolina/metabolismo , Animais , Transtorno Bipolar/metabolismo , Transtorno Bipolar/terapia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/terapia , Humanos , Transtornos Mentais/terapia , Esquizofrenia/metabolismo , Esquizofrenia/terapiaRESUMO
Schizophrenia is widely acknowledged as being a syndrome, consisting of an undefined number of diseases probably with differing pathologies. Although studying a syndrome makes the identification of an underlying pathology more difficult; neuroimaging, neuropsychopharmacological and post-mortem brain studies all implicate muscarinic acetylcholine receptors (CHRM) in the pathology of the disorder. We have established that the CHRM1 is selectively decreased in the dorsolateral prefrontal cortex of subjects with schizophrenia. To expand this finding, we wanted to ascertain whether decreased cortical CHRMs might (1) define a subgroup of schizophrenia and/or (2) be related to CHRM1 genotype. We assessed cortical [(3)H]pirenzepine binding and sequenced the CHRM1 in 80 subjects with schizophrenia and 74 age sex-matched control subjects. Kernel density estimation showed that [(3)H]pirenzepine binding in BA9 divided the schizophrenia, but not control, cohort into two distinct populations. One of the schizophrenia cohorts, comprising 26% of all subjects with the disorder, had a 74% reduction in mean cortical [(3)H]pirenzepine binding compared to controls. We suggest that these individuals make up 'muscarinic receptor-deficit schizophrenia' (MRDS). The MRDS could not be separated from other subjects with schizophrenia by CHRM1 sequence, gender, age, suicide, duration of illness or any particular drug treatment. Being able to define a subgroup within schizophrenia using a central biological parameter is a pivotal step towards understanding the biochemistry underlying at least one form of the disorder and may represent a biomarker that can be used in neuroimaging.
Assuntos
Regulação para Baixo/fisiologia , Córtex Pré-Frontal/metabolismo , Receptor Muscarínico M1/metabolismo , Esquizofrenia/classificação , Esquizofrenia/patologia , Adulto , Análise de Variância , Distribuição de Qui-Quadrado , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/farmacologia , Pirenzepina/metabolismo , Pirenzepina/farmacologia , Mudanças Depois da Morte , Ligação Proteica/efeitos dos fármacos , Receptor Muscarínico M1/genética , Esquizofrenia/metabolismo , Trítio/metabolismoRESUMO
BACKGROUND: Dysfunction of the cholinergic muscarinic receptors has been implicated in the pathology of bipolar disorder and major depressive disorder. However, there is conflicting evidence regarding the association between individual muscarinic receptors and the two disorders. METHODS: We used the muscarinic receptor selective radioligands [3H]pirenzepine, [3H]AFDX-384 and [3H]4-DAMP to measure the levels of muscarinic(1) (CHRM1) and muscarinic(4) (CHRM4) receptors, muscarinic(2) (CHRM2) and muscarinic(4) (CHRM4) receptors and muscarinic(3) (CHRM3) receptor, respectively. Radioligand binding was measured in Brodmann's area (BA) 10 of the rostral prefrontal cortex, BA 46 of the dorsolateral prefrontal cortex and BA 40 of the parietal cortex in the post-mortem CNS from subjects with bipolar disorder or major depressive disorder and control subjects. RESULTS: [3H]AFDX-384 binding was decreased in BA 46 in both bipolar disorder (p<0.01) and major depressive disorder (p<0.05). [3H]4-DAMP binding was decreased in BA 10 in bipolar disorder (p<0.05) but not major depressive disorder (p>0.05). [3H]AFDX-384 and [3H]4-DAMP binding were unaltered in any other cortical region examined for either disorder (p>0.05). [3H]pirenzepine binding was not significantly altered in either disorder in any cortical region examined (p>0.05). LIMITATIONS: 9 bipolar disorder, 9 major depressive disorder and 19 control subjects were used in the study. CONCLUSION: Our data is consistent with previously published data implicating a role for CHRM2 receptors in the pathology of bipolar and major depressive disorder. The demonstration of a novel association between decreased CHRM3 receptor expression and bipolar disorder suggests bipolar and major depressive disorder differs in the underlying nature of their cholinergic dysfunction.
Assuntos
Transtorno Bipolar/metabolismo , Transtorno Depressivo Maior/metabolismo , Lobo Frontal/metabolismo , Receptores Muscarínicos/metabolismo , Adulto , Idoso , Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Nicotínicos/metabolismo , Tentativa de Suicídio/estatística & dados numéricos , Adulto JovemRESUMO
Phospholipase C-beta1 (PLC-beta1) is a rate-limiting enzyme implicated in postnatal-cortical development and neuronal plasticity. PLC-beta1 transduces intracellular signals from specific muscarinic, glutamate and serotonin receptors, all of which have been implicated in the pathogenesis of schizophrenia. Here, we present data to show that PLC-beta1 knockout mice display locomotor hyperactivity, sensorimotor gating deficits as well as cognitive impairment. These changes in behavior are regarded as endophenotypes homologous to schizophrenia-like symptoms in rodents. Importantly, the locomotor hyperactivity and sensorimotor gating deficits in PLC-beta1 knockout mice are subject to beneficial modulation by environmental enrichment. Furthermore, clozapine but not haloperidol (atypical and typical antipsychotics, respectively) rescues the sensorimotor gating deficit in these animals, suggesting selective predictive validity. We also demonstrate a relationship between the beneficial effects of environmental enrichment and levels of M1/M4 muscarinic acetylcholine receptor binding in the neocortex and hippocampus. Thus we have demonstrated a novel mouse model, displaying disruption of multiple postsynaptic signals implicated in the pathogenesis of schizophrenia, a relevant behavioral phenotype and associated gene-environment interactions.
Assuntos
Clozapina/uso terapêutico , Fosfolipase C beta/deficiência , Esquizofrenia/genética , Esquizofrenia/reabilitação , Animais , Antipsicóticos/uso terapêutico , Modelos Animais de Doenças , Meio Ambiente , Hipocampo/fisiopatologia , Camundongos , Camundongos Knockout , Atividade Motora , Neocórtex/fisiopatologia , Fenótipo , Receptores Muscarínicos/fisiologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/enzimologia , Psicologia do EsquizofrênicoRESUMO
OBJECTIVE: In order to identify whether the mechanisms associated with neurotransmitter release are involved in the pathologies of bipolar disorder and schizophrenia, levels of presynaptic [synaptosomal-associated protein-25 (SNAP-25), syntaxin, synaptophysin, vesicle-associated membrane protein, dynamin I] and structural (neuronal cell adhesion molecule and alpha-synuclein) neuronal markers were measured in Brodmann's area 9 obtained postmortem from eight subjects with bipolar I disorder (BPDI), 20 with schizophrenia and 20 controls. METHODS: Determinations of protein levels were carried out using Western blot techniques with specific antibodies. Levels of mRNA were measured using real-time polymerase chain reaction. RESULTS: In BPDI, levels of SNAP-25 (p < 0.01) and synaptophysin (p < 0.05) increased. There were no changes in schizophrenia or any other changes in BPDI. Levels of mRNA for SNAP-25 were decreased in BPDI (p < 0.05). CONCLUSION: Changes in SNAP-25 and synaptophysin in BPDI suggest that changes in specific neuronal functions could be linked to the pathology of the disorder.