RESUMO
The glutamate hypothesis of schizophrenia proposes that abnormal glutamatergic neurotransmission occurs in this illness, and a major contribution may involve dysregulation of the AMPA subtype of ionotropic glutamate receptor (AMPAR). Transmembrane AMPAR regulatory proteins (TARPs) form direct associations with AMPARs to modulate the trafficking and biophysical functions of these receptors, and their dysregulation may alter the localization and activity of AMPARs, thus having a potential role in the pathophysiology of schizophrenia. We performed comparative quantitative real-time PCR and Western blot analysis to measure transcript (schizophrenia, N=25; comparison subjects, N=25) and protein (schizophrenia, N=36; comparison subjects, N=33) expression of TARPs (γ subunits 1-8) in the anterior cingulate cortex (ACC) in schizophrenia and a comparison group. TARP expression was also measured in frontal cortex of rats chronically treated with haloperidol decanoate (28.5mg/kg every three weeks for nine months) to determine the effect of antipsychotic treatment on the expression of these molecules. We found decreased transcript expression of TARP γ-8 in schizophrenia. At the protein level, γ-3 and γ-5 were increased, while γ-4, γ-7 and γ-8 were decreased in schizophrenia. No changes in any of the molecules were noted in the frontal cortex of haloperidol-treated rats. TARPs are abnormally expressed at transcript and protein levels in ACC in schizophrenia, and these changes are likely due to the illness and not to the antipsychotic treatment. Alterations in the expression of TARPs may contribute to the pathophysiology of schizophrenia, and represent a potential mechanism of glutamatergic dysregulation in this illness.
Assuntos
Regulação da Expressão Gênica/fisiologia , Giro do Cíngulo/metabolismo , Proteínas Nucleares/metabolismo , Esquizofrenia/patologia , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Animais , Antipsicóticos/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Haloperidol/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Mudanças Depois da Morte , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Glutamate transporters facilitate the buffering, clearance and cycling of glutamate and play an important role in maintaining synaptic and extrasynaptic glutamate levels. Alterations in glutamate transporter expression may lead to abnormal glutamate neurotransmission contributing to the pathophysiology of schizophrenia. In addition, alterations in the architecture of the superior temporal gyrus and hippocampus have been implicated in this illness, suggesting that synapses in these regions may be remodeled from a lifetime of severe mental illness and antipsychotic treatment. Thus, we hypothesize that glutamate neurotransmission may be abnormal in the superior temporal gyrus and hippocampus in schizophrenia. To test this hypothesis, we examined protein expression of excitatory amino acid transporter 1-3 and vesicular glutamate transporter 1 and 2 in subjects with schizophrenia (n=23) and a comparison group (n=27). We found decreased expression of EAAT1 and EAAT2 protein in the superior temporal gyrus, and decreased EAAT2 protein in the hippocampus in schizophrenia. We didn't find any changes in expression of the neuronal transporter EAAT3 or the presynaptic vesicular glutamate transporters VGLUT1-2. In addition, we did not detect an effect of antipsychotic medication on expression of EAAT1 and EAAT2 proteins in the temporal association cortex or hippocampus in rats treated with haloperidol for 9 months. Our findings suggest that buffering and reuptake, but not presynaptic release, of glutamate is altered in glutamate synapses in the temporal lobe in schizophrenia.
Assuntos
Proteínas de Transporte de Glutamato da Membrana Plasmática/biossíntese , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Esquizofrenia/metabolismo , Lobo Temporal/metabolismo , Proteínas Vesiculares de Transporte de Glutamato/biossíntese , Idoso , Idoso de 80 Anos ou mais , Animais , Antipsicóticos/administração & dosagem , Modelos Animais de Doenças , Transportador 1 de Aminoácido Excitatório/biossíntese , Transportador 1 de Aminoácido Excitatório/genética , Transportador 2 de Aminoácido Excitatório/biossíntese , Transportador 2 de Aminoácido Excitatório/genética , Transportador 3 de Aminoácido Excitatório/biossíntese , Transportador 3 de Aminoácido Excitatório/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Transporte de Glutamato da Membrana Plasmática/genética , Ácido Glutâmico/genética , Haloperidol/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/patologia , Proteína Vesicular 1 de Transporte de Glutamato/biossíntese , Proteína Vesicular 1 de Transporte de Glutamato/genética , Proteína Vesicular 2 de Transporte de Glutamato/biossíntese , Proteína Vesicular 2 de Transporte de Glutamato/genética , Proteínas Vesiculares de Transporte de Glutamato/genéticaRESUMO
Schizophrenia has been proposed to be associated with abnormal glutamatergic neurotransmission. The AMPA subtype of glutamate receptors (AMPARs) mediates fast excitatory synaptic transmission in the brain, and their trafficking and function is regulated in part by AMPAR auxiliary proteins including the cornichons (CNIH) and transmembrane AMPAR-regulatory proteins. Abnormal regulation of AMPARs through altered expression of these auxiliary proteins could induce changes in glutamatergic neurotransmission and thus the pathophysiology of schizophrenia. In this study, transcript expression of cornichon homologs 1-4 was measured in the dorsolateral prefrontal cortex from schizophrenia (N=25) and comparison (N=25) patient groups by comparative quantitative real-time PCR. Significant upregulation of CNIH-1, CNIH-2, and CNIH-3 mRNA expression was found in schizophrenia, with no change in CNIH-4 expression. To determine the effect of antipsychotic treatment on the expression of these genes, cornichon mRNA expression was assayed in the frontal cortex of rats treated chronically with haloperidol decanoate and no changes in any of the cornichon transcripts were found. Abnormal expression of the CNIH family of genes is consistent with cornichon-mediated AMPAR trafficking abnormalities in schizophrenia, and suggests a new mechanism contributing toward the pathophysiology of this illness.
Assuntos
Proteínas do Ovo/genética , Regulação da Expressão Gênica , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/biossíntese , Receptores de AMPA/genética , Esquizofrenia/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Antipsicóticos/farmacologia , Proteínas do Ovo/biossíntese , Feminino , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Marcadores Genéticos , Predisposição Genética para Doença , Ácido Glutâmico/fisiologia , Haloperidol/análogos & derivados , Haloperidol/farmacologia , Humanos , Masculino , Proteínas de Membrana/biossíntese , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/biossíntese , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/biossíntese , Esquizofrenia/metabolismo , Transmissão Sináptica , Regulação para Cima/efeitos dos fármacosRESUMO
Schizophrenia is a devastating psychiatric illness that afflicts 1% of the population worldwide, resulting in substantial impact to patients, their families, and health care delivery systems. For many years, schizophrenia has been felt to be associated with dysregulated dopaminergic neurotransmission as a key feature of the pathophysiology of the illness. Although numerous studies point to dopaminergic abnormalities in schizophrenia, dopamine dysfunction cannot completely account for all of the symptoms seen in schizophrenia, and dopamine-based treatments are often inadequate and can be associated with serious side effects. More recently, converging lines of evidence have suggested that there are abnormalities of glutamate transmission in schizophrenia. Glutamatergic neurotransmission involves numerous molecules that facilitate glutamate release, receptor activation, glutamate reuptake, and other synaptic activities. Evidence for glutamatergic abnormalities in schizophrenia primarily has implicated the NMDA and AMPA subtypes of the glutamate receptor. The expression of these receptors and other molecules associated with glutamate neurotransmission has been systematically studied in the brain in schizophrenia. These studies have generally revealed region- and molecule-specific changes in glutamate receptor transcript and protein expression in this illness. Given that glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia, recent drug development efforts have targeted the glutamate system. Much effort to date has focused on modulation of the NMDA receptor, although more recently other glutamate receptors and transporters have been the targets of drug development. These efforts have been promising thus far, and ongoing efforts to develop additional drugs that modulate glutamatergic neurotransmission are underway that may hold the potential for novel classes of more effective treatments for this serious psychiatric illness.