RESUMEN
Reduced hippocampal volume is a consistent finding in neuroimaging studies of individuals with schizophrenia. While these studies have the advantage of large-sample sizes, they are unable to quantify the cellular basis of structural or functional changes. In contrast, postmortem studies are well suited to explore subfield and cellular alterations, but low sample sizes and subject heterogeneity impede establishment of statistically significant differences. Here we use a meta-analytic approach to synthesize the extant literature of hippocampal subfield volume and cellular composition in schizophrenia patients and healthy control subjects. Following pre-registration (PROSPERO CRD42019138280), PubMed, Web of Science, and PsycINFO were searched using the term: (schizophrenia OR schizoaffective) AND (post-mortem OR postmortem) AND hippocampus. Subjects were adult men and women with schizophrenia or schizoaffective disorder or non-psychiatric control subjects, and key outcomes, stratified by hippocampal hemisphere and subfield, were volume, neuron number, neuron density, and neuron size. A random effects meta-analysis was performed. Thirty-two studies were included (413 patients, 415 controls). In patients, volume and neuron number were significantly reduced in multiple hippocampal subfields in left, but not right hippocampus, whereas neuron density was not significantly different in any hippocampal subfield. Neuron size, averaged bilaterally, was also significantly reduced in all calculated subfields. Heterogeneity was minimal to moderate, with rare evidence of publication bias. Meta-regression of age and illness duration did not explain heterogeneity of total hippocampal volume effect sizes. These results extend neuroimaging findings of smaller hippocampal volume in schizophrenia patients and further our understanding of regional and cellular neuropathology in schizophrenia.
Asunto(s)
Esquizofrenia , Adulto , Femenino , Hipocampo , Humanos , Imagen por Resonancia Magnética , Masculino , Neuronas , Tamaño de los ÓrganosRESUMEN
Rapid release of neurotransmitters in synchrony with action potentials is considered a key hardwired property of synapses. Here, in glutamatergic synapses formed between induced human neurons, we show that action potential-dependent neurotransmitter release becomes progressively desynchronized as synapses mature and age. In this solely excitatory network, the emergence of NMDAR-mediated transmission elicits endoplasmic reticulum (ER) stress leading to downregulation of key presynaptic molecules, synaptotagmin-1 and cysteine string protein α, that synchronize neurotransmitter release. The emergence of asynchronous release with neuronal maturity and subsequent aging is maintained by the high-affinity Ca2+ sensor synaptotagmin-7 and suppressed by the introduction of GABAergic transmission into the network, inhibition of NMDARs, and ER stress. These results suggest that long-term disruption of excitation-inhibition balance affects the synchrony of excitatory neurotransmission in human synapses.
Asunto(s)
Neuronas , Transmisión Sináptica , Humanos , Neuronas/metabolismo , Transmisión Sináptica/fisiología , Sinapsis/metabolismo , Neurotransmisores/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Envejecimiento , Calcio/metabolismoRESUMEN
Gene expression studies of bipolar disorder (BPD) have shown changes in transcriptome profiles in multiple brain regions. Here we summarize the most consistent findings in the scientific literature, and compare them to data from schizophrenia (SZ) and major depressive disorder (MDD). The transcriptome profiles of all three disorders overlap, making the existence of a BPD-specific profile unlikely. Three groups of functionally related genes are consistently expressed at altered levels in BPD, SZ and MDD. Genes involved in energy metabolism and mitochondrial function are downregulated, genes involved in immune response and inflammation are upregulated, and genes expressed in oligodendrocytes are downregulated. Experimental paradigms for multiple sclerosis demonstrate a tight link between energy metabolism, inflammation and demyelination. These studies also show variabilities in the extent of oligodendrocyte stress, which can vary from a downregulation of oligodendrocyte genes, such as observed in psychiatric disorders, to cell death and brain lesions seen in multiple sclerosis. We conclude that experimental models of multiple sclerosis could be of interest for the research of BPD, SZ and MDD.
Asunto(s)
Trastorno Bipolar/genética , Inflamación/genética , Mitocondrias/genética , Esclerosis Múltiple/genética , Oligodendroglía/metabolismo , Trastorno Bipolar/metabolismo , Perfilación de la Expresión Génica , Humanos , Inflamación/metabolismo , Mitocondrias/metabolismo , Esclerosis Múltiple/metabolismo , TranscriptomaRESUMEN
Angiogenesis and increased permeability of the blood-brain barrier have been reported to occur in animal models of Parkinson's disease and l-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of l-dopa-induced dyskinesia, this study demonstrates that chronic treatment with l-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with l-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood-brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson's disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of l-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of l-dopa pharmacotherapy in Parkinson's disease.
Asunto(s)
Antiparkinsonianos/efectos adversos , Encéfalo/efectos de los fármacos , Discinesia Inducida por Medicamentos/etiología , Levodopa/efectos adversos , Trastornos Parkinsonianos/patología , Regulación hacia Arriba/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Animales , Antígenos CD/metabolismo , Antígenos de Superficie/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Conducta Animal/efectos de los fármacos , Benserazida/efectos adversos , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/fisiopatología , Encéfalo/citología , Bromodesoxiuridina/metabolismo , Recuento de Células , Células Cultivadas , Modelos Animales de Enfermedad , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/patología , Embrión de Mamíferos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Laminina/metabolismo , Masculino , Neovascularización Patológica/inducido químicamente , Neovascularización Patológica/tratamiento farmacológico , Proteínas del Tejido Nervioso/metabolismo , Trastornos Parkinsonianos/tratamiento farmacológico , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
GABAergic interneurons synchronize network activities and monitor information flow. Post-mortem studies have reported decreased densities of cortical interneurons in schizophrenia (SZ) and bipolar disorder (BPD). The entorhinal cortex (EC) and the adjacent subicular regions are a hub for integration of hippocampal and cortical information, a process that is disrupted in SZ. Here we contrast and compare the density of interneuron populations in the caudal EC and subicular regions in BPD type I (BPD-I), SZ, and normal control (NC) subjects. Post-mortem human parahippocampal specimens of 13 BPD-I, 11 SZ and 17 NC subjects were used to examine the numerical density of parvalbumin-, somatostatin- or calbindin-positive interneurons. We observed a reduction in the numerical density of parvalbumin- and somatostatin-positive interneurons in the caudal EC and parasubiculum in BPD-I and SZ, but no change in the subiculum. Calbindin-positive interneuron densities were normal in all brain areas examined. The profile of decreased density was strikingly similar in BPD-I and SZ. Our results demonstrate a specific reduction of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region in BPD-I and SZ, likely disrupting synchronization and integration of cortico-hippocampal circuits.
Asunto(s)
Trastorno Bipolar/patología , Interneuronas/metabolismo , Interneuronas/patología , Giro Parahipocampal/patología , Parvalbúminas/metabolismo , Esquizofrenia/patología , Somatostatina/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autopsia , Trastorno Bipolar/metabolismo , Calbindinas , Estudios de Casos y Controles , Recuento de Células , Corteza Entorrinal/metabolismo , Corteza Entorrinal/patología , Femenino , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Masculino , Persona de Mediana Edad , Red Nerviosa/metabolismo , Red Nerviosa/patología , Giro Parahipocampal/metabolismo , Proteína G de Unión al Calcio S100/metabolismo , Esquizofrenia/metabolismo , Adulto JovenRESUMEN
Parvalbumin-expressing interneurons (PV-INs) are highly vulnerable to stressors and have been implicated in many neuro-psychiatric diseases such as schizophrenia, Alzheimer's disease, autism spectrum disorder, and bipolar disorder. We examined the literature about the current knowledge of the physiological properties of PV-INs and gathered results from diverse research areas to provide insight into their vulnerability to stressors. Among the factors that confer heightened vulnerability are the substantial energy requirements, a strong excitatory drive, and a unique developmental trajectory. Understanding these stressors and elaborating on their impact on PV-IN health is a step toward developing therapies to protect these neurons in various disease states and to retain critical brain functions.
Asunto(s)
Enfermedad de Alzheimer , Trastorno del Espectro Autista , Humanos , Interneuronas , Neuronas , ParvalbúminasRESUMEN
Prolonged treatment of Parkinson's disease (PD) with levodopa leads to disabling side effects collectively referred to as 'dyskinesias'. We hypothesized that bioenergetic function in the putamen might play a crucial role in the development of dyskinesias. To test this hypothesis, we used post mortem samples of the human putamen and applied real time-PCR approaches and gene expression microarrays. We found that mitochondrial DNA (mtDNA) levels are decreased in patients who have developed dyskinesias, and mtDNA damage is concomitantly increased. These pathologies were not observed in PD subjects without signs of dyskinesias. The group of nuclear mRNA transcripts coding for the proteins of the mitochondrial electron transfer chain was decreased in patients with dyskinesias to a larger extent than in patients who had not developed dyskinesias. To examine whether dopamine fluctuations affect mtDNA levels in dopaminoceptive neurons, rat striatal neurons in culture were repeatedly exposed to levodopa, dopamine or their metabolites. MtDNA levels were reduced after treatment with dopamine, but not after treatment with dopamine metabolites. Levodopa led to an increase in mtDNA levels. We conclude that mitochondrial susceptibility in the putamen plays a role in the development of dyskinesias.
Asunto(s)
Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/patología , Mitocondrias/patología , Enfermedad de Parkinson/patología , Putamen/patología , Animales , Cromatografía Líquida de Alta Presión , ADN Mitocondrial/efectos de los fármacos , Dopamina/efectos adversos , Dopamina/metabolismo , Humanos , Levodopa/efectos adversos , Levodopa/metabolismo , Masculino , Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Enfermedad de Parkinson/tratamiento farmacológico , Putamen/efectos de los fármacos , ARN/efectos de los fármacos , ARN Mitocondrial , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The nucleus accumbens (NAc) is a critical brain area for reward and motivated behavior. Accumulating evidence suggests that altered function of the transcription factor cAMP response element binding protein (CREB) within the NAc is involved in depressive behavior. In rats, stress activates CREB within the NAc, and elevation of CREB expression in this region produces depressive-like behaviors that are accompanied by activation of CREB-regulated target genes. The depressive-like behaviors seem to be due, at least in part, to CREB-mediated increases in dynorphin function, because they are mimicked by kappa-opioid receptor (KOR) agonists and attenuated by KOR antagonists. We hypothesized that if CREB-mediated dynorphin expression in the NAc contributes to depressive behavior, then antidepressants might reduce dynorphin function in this region. Here, we demonstrate that desipramine (DMI), a norepinephrine reuptake inhibitor that has been used for decades to treat clinical depression, blocks swim stress-induced activation of prodynorphin (encodes dynorphin) in the NAc. In primary cultures of NAc and striatum, DMI decreases basal and stimulated CREB phosphorylation by causing reductions in intracellular calcium (Ca(2+)) availability that are independent of norepinephrine or other monoaminergic inputs, identifying a potential mechanism for alterations in CREB-mediated gene expression. Fluoxetine (FLX), a selective serotonin reuptake inhibitor, has similar effects in culture, suggesting a common intracellular effect of these antidepressants. These findings raise the possibility that a therapeutically relevant mechanism of action of DMI occurs through attenuation of CREB-mediated gene transcription, which is mediated via previously uncharacterized mechanisms that occur directly within the NAc.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/antagonistas & inhibidores , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Desipramina/farmacología , Dinorfinas/antagonistas & inhibidores , Dinorfinas/biosíntesis , Núcleo Accumbens/metabolismo , Estrés Fisiológico/fisiología , Animales , Células Cultivadas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Dinorfinas/genética , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Masculino , Núcleo Accumbens/efectos de los fármacos , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Embarazo , Ratas , Ratas Sprague-Dawley , Estrés Fisiológico/efectos de los fármacosRESUMEN
CONTEXT: Bipolar disorder (BPD) is among the top 10 causes of disability worldwide. Recent findings on the etiology of the disease point to a disturbed mitochondrial energy metabolism in the brain of subjects with BPD. OBJECTIVE: To test whether gene transcripts for proteins of the mitochondrial respiratory chain have altered levels in glucose-deprived lymphocytes from patients with BPD. DESIGN: Microarrays were used to measure gene expression levels in fresh lymphocytes and in lymphocytes cultured for 5 days in regular or low-glucose medium. SETTING: Subjects with BPD were recruited through the Schizophrenia and Bipolar Disorders Program, McLean Hospital, Belmont, Mass. Controls were recruited through advertising. Patients A total of 21 patients with BPD (inpatients and outpatients) and 21 control subjects. Main Outcome Measure Expression levels for genes of proteins involved in mitochondrial respiration. RESULTS: We found an opposite molecular response of control and BPD lymphocytes to glucose deprivation. Whereas lymphocytes of normal controls responded to glucose deprivation with an up-regulation of nuclear transcripts for proteins of the electron transfer chain, subjects with BPD had a tendency to down-regulate these transcripts. CONCLUSIONS: The results suggest that the normal molecular adaptation to energy stress is deficient in lymphocytes from patients with BPD.
Asunto(s)
Trastorno Bipolar/genética , Trastorno Bipolar/metabolismo , Proteínas del Complejo de Cadena de Transporte de Electrón/efectos de los fármacos , Proteínas del Complejo de Cadena de Transporte de Electrón/genética , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Metabolismo Energético/genética , Glucosa/metabolismo , Linfocitos/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Adulto , Trastorno Bipolar/sangre , Glucemia/análisis , Glucemia/metabolismo , Células Cultivadas , Regulación hacia Abajo , Transporte de Electrón/efectos de los fármacos , Transporte de Electrón/genética , Metabolismo Energético/fisiología , Femenino , Perfilación de la Expresión Génica , Genes Supresores de Tumor , Humanos , Linfocitos/citología , Masculino , Persona de Mediana Edad , Proteínas Nucleares , Análisis por Matrices de ProteínasAsunto(s)
Magnoliopsida , Trastornos Psicóticos , Animales , Polinización , Aislamiento Reproductivo , Modelos AnimalesRESUMEN
Drugs of abuse alter expression of AMPA-type glutamate receptor subunits (GluRs) in the nucleus accumbens (NAc), a key component of brain reward systems. The impact of this regulation on general motivational states is unclear. Here, we used herpes simplex virus vectors to examine how transient increases in the expression of GluR1 or GluR2 protein in the shell component of NAc affect the rewarding impact of electrical stimulation of the medial forebrain bundle, as reflected by intracranial self-stimulation (ICSS) thresholds in rats. We found that elevated GluR1 in NAc shell increases ICSS thresholds, an effect similar to that caused by treatments that cause anhedonia and dysphoria (prodepressive effects) in rats and humans (e.g., drug withdrawal, kappa-opioid agonists). In contrast, elevated GluR2 decreases ICSS thresholds, an effect similar to that caused by rewarding treatments (e.g., drugs of abuse). To confirm that viral vector-mediated elevations of GluR1 in the NAc shell produce molecular consequences that are different from those of elevated GluR2, we examined the expression of a set of drug-regulated genes 3 d after treatment using quantitative PCR. Elevated GluR1 was accompanied by sustained increases in the gene for GluR1, whereas elevated GluR2 was accompanied by decreases in prodynorphin. These data suggest that GluR1 and GluR2 in the NAc shell play opposing roles in the regulation of motivated behavior.
Asunto(s)
Núcleo Accumbens/fisiología , Receptores AMPA/fisiología , Recompensa , Análisis de Varianza , Animales , Conducta Animal , Estimulación Eléctrica/métodos , Expresión Génica/fisiología , Vectores Genéticos/fisiología , Masculino , Haz Prosencefálico Medial/fisiología , Haz Prosencefálico Medial/efectos de la radiación , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Autoadministración/métodos , Simplexvirus/fisiología , Factores de TiempoRESUMEN
Illicit use of drugs frequently begins and escalates during adolescence, with long-term adverse consequences. Because it is increasingly accepted that neural development continues through adolescence, addiction research has become more invested in understanding the behavioral and molecular consequences of early exposure to drugs of abuse. In a novel binge administration paradigm designed to model the pattern of human adolescent drug use, we administered ascending doses of cocaine or saline during a 12-d developmental period [postnatal day 35 (P35) to P46] corresponding to human adolescence. During adulthood (P70), rats treated with this regimen displayed increased responsiveness to the stimulant effects of cocaine. Adult rats also displayed abnormally rapid shifts in attention when performing an attentional set-shifting task, which measures the ability to shift attention between stimuli and whose performance requires an intact prefrontal cortex (PFC). Treatment with cocaine during adolescence also caused acute alterations in the expression of genes encoding cell adhesion molecules and transcription factors within the PFC. Furthermore, we observed decreases in histone methylation, which may indicate a role for chromatin remodeling in the observed changes in gene expression patterns. These findings suggest that exposure to cocaine during adolescence has far-reaching molecular and behavioral consequences in the rat PFC that develop over time and endure long after drug administration has ceased.
Asunto(s)
Atención/efectos de los fármacos , Cocaína/administración & dosificación , Regulación de la Expresión Génica/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Factores de Edad , Animales , Atención/fisiología , Conducta Adictiva/metabolismo , Conducta Adictiva/psicología , Regulación de la Expresión Génica/fisiología , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Lithium (Li) is frequently used in the treatment of bipolar disorder (BPD), a debilitating condition that is increasingly diagnosed in children and adolescents. Because the symptoms of BPD in children are different from the typical symptoms in adulthood and have significant overlap with other childhood psychiatric disorders, this disorder is notoriously difficult to diagnose. This raises the possibility that some children not affected by BPD are treated with Li during key periods of brain development. The objective of this investigation was to examine the long-term effects of Li on the developing brain via a series of behavioral and molecular studies in rats. Rat pups were reared on Li chow for 3 weeks. Parallel groups were tested while on Li chow or 2 and 6 weeks after discontinuation of treatment. We found increased measures of anxiety-like behavior at all times tested. Gene microarray studies of the amygdala revealed that Li affected the expression of gene transcripts of the synapse and the cytoskeleton, suggesting that the treatment induced synaptic adjustments. Our study indicates that Li can alter the trajectory of brain development. Although the effects of Li on the normal brain seems unfavorable, effects on the abnormal brain cannot be determined from these studies alone and may well be therapeutic. Our results indicate that Li administration to the normal brain has the potential for lasting adverse effects.
Asunto(s)
Ansiedad/inducido químicamente , Litio/farmacología , Administración Oral , Adulto , Animales , Trastorno Bipolar/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Niño , Modelos Animales de Enfermedad , Miedo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Litio/administración & dosificación , Litio/uso terapéutico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN/genética , ARN/aislamiento & purificación , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacosRESUMEN
BACKGROUND: We examined the activation pattern of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and its dependence on D1 versus D2 dopamine receptors in hemiparkinsonian rats treated with 3,4-dihydroxyphenyl-L-alanine (L-DOPA). METHODS: 6-Hydroxydopamine-lesioned rats were treated acutely or chronically with L-DOPA in combination with antagonists for D1 or D2 receptors. Development of dyskinesia was monitored in animals receiving chronic drug treatment. Phosphorylation of ERK1/2, mitogen- and stress-activated protein kinase-1 (MSK-1), and the levels of FosB/DeltaFosB expression were examined immunohistochemically. RESULTS: L-DOPA treatment caused phosphorylation of ERK1/2 in the dopamine-denervated striatum after acute and chronic administration. Similar levels were observed in matrix and striosomes, and in enkephalin-positive and dynorphin-positive neurons. The severity of dyskinesia was positively correlated with phospho-ERK1/2 levels. Phosphorylation of ERK1/2 and MSK-1 was dose-dependently blocked by SCH23390, but not by raclopride. SCH23390 also inhibited the development of dyskinesia and the induction of FosB/DeltaFosB. CONCLUSIONS: L-DOPA produces pronounced activation of ERK1/2 signaling in the dopamine-denervated striatum through a D1-receptor-dependent mechanism. This effect is associated with the development of dyskinesia. Phosphorylated ERK1/2 is localized to both dynorphinergic and enkephalinergic striatal neurons, suggesting a general role of ERK1/2 as a plasticity molecule during L-DOPA treatment.
Asunto(s)
Dopaminérgicos , Discinesia Inducida por Medicamentos/fisiopatología , Levodopa , Proteína Quinasa 1 Activada por Mitógenos/fisiología , Proteína Quinasa 3 Activada por Mitógenos/fisiología , Neostriado/anatomía & histología , Neostriado/enzimología , Receptores de Dopamina D1/fisiología , Animales , Benzazepinas/farmacología , Recuento de Células , Desnervación , Antagonistas de Dopamina/farmacología , Dinorfinas/fisiología , Encefalinas/fisiología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Femenino , Técnica del Anticuerpo Fluorescente , Inmunohistoquímica , Hibridación in Situ , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neuronas Eferentes/efectos de los fármacos , Neuronas Eferentes/fisiología , Fosforilación , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/fisiologíaRESUMEN
Mitochondrial DNA (mtDNA), the discrete genome which encodes subunits of the mitochondrial respiratory chain, is present at highly variable copy numbers across cell types. Though severe mtDNA depletion dramatically reduces mitochondrial function, the impact of tissue-specific mtDNA reduction remains debated. Previously, our lab identified reduced mtDNA quantity in the putamen of Parkinson's Disease (PD) patients who had developed L-DOPA Induced Dyskinesia (LID), compared to PD patients who had not developed LID and healthy subjects. Here, we present the consequences of mtDNA depletion by ethidium bromide (EtBr) treatment on the bioenergetic function of primary cultured neurons, astrocytes and neuron-enriched cocultures from rat striatum. We report that EtBr inhibition of mtDNA replication and transcription consistently reduces mitochondrial oxygen consumption, and that neurons are significantly more sensitive to EtBr than astrocytes. EtBr also increases glycolytic activity in astrocytes, whereas in neurons it reduces the expression of mitochondrial creatine kinase mRNA and levels of phosphocreatine. Further, we show that mitochondrial creatine kinase mRNA is similarly downregulated in dyskinetic PD patients, compared to both non-dyskinetic PD patients and healthy subjects. Our data support a hypothesis that reduced striatal mtDNA contributes to energetic dysregulation in the dyskinetic striatum by destabilizing the energy buffering system of the phosphocreatine/creatine shuttle.
Asunto(s)
Cuerpo Estriado/metabolismo , Creatina Quinasa/metabolismo , ADN Mitocondrial/metabolismo , Metabolismo Energético , Etidio/farmacología , Mitocondrias/enzimología , Animales , Células Cultivadas , Glucólisis , Humanos , Consumo de Oxígeno , Ratas , Ratas Sprague-DawleyRESUMEN
Cholesterol metabolism is vital for brain function. Previous work in cultured cells has shown that a number of psychotropic drugs inhibit the activity of 7-dehydrocholesterol reductase (DHCR7), an enzyme that catalyzes the final steps in cholesterol biosynthesis. This leads to the accumulation of 7-dehydrocholesterol (7DHC), a molecule that gives rise to oxysterols, vitamin D, and atypical neurosteroids. We examined levels of cholesterol and the cholesterol precursors desmosterol, lanosterol, 7DHC and its isomer 8-dehydrocholesterol (8DHC), in blood samples of 123 psychiatric patients on various antipsychotic and antidepressant drugs, and 85 healthy controls, to see if the observations in cell lines hold true for patients as well. Three drugs, aripiprazole, haloperidol and trazodone increased circulating 7DHC and 8DHC levels, while five other drugs, clozapine, escitalopram/citalopram, lamotrigine, olanzapine, and risperidone, did not. Studies in rat brain verified that haloperidol dose-dependently increased 7DHC and 8DHC levels, while clozapine had no effect. We conclude that further studies should investigate the role of 7DHC and 8DHC metabolites, such as oxysterols, vitamin D, and atypical neurosteroids, in the deleterious and therapeutic effects of psychotropic drugs. Finally, we recommend that drugs that increase 7DHC levels should not be prescribed during pregnancy, as children born with DHCR7 deficiency have multiple congenital malformations.
Asunto(s)
Antidepresivos/efectos adversos , Antidepresivos/uso terapéutico , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Colestadienoles/sangre , Deshidrocolesteroles/sangre , Adulto , Animales , Antidepresivos/farmacología , Antipsicóticos/farmacología , Índice de Masa Corporal , Clozapina/efectos adversos , Clozapina/farmacología , Clozapina/uso terapéutico , Femenino , Haloperidol/efectos adversos , Haloperidol/farmacología , Haloperidol/uso terapéutico , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Trastornos Mentales/sangre , Trastornos Mentales/tratamiento farmacológico , Escalas de Valoración Psiquiátrica , Distribución Aleatoria , Ratas Sprague-Dawley , Aumento de Peso/efectos de los fármacosRESUMEN
In rodent and human brains, the small GTP-binding protein Rhes is highly expressed in virtually all dopaminoceptive striatal GABAergic medium spiny neurons, as well as in large aspiny cholinergic interneurons, where it is thought to modulate dopamine-dependent signaling. Consistent with this knowledge, and considering that dopaminergic neurotransmission is altered in neurological and psychiatric disorders, here we sought to investigate whether Rhes mRNA expression is altered in brain regions of patients with Parkinson's disease (PD), Schizophrenia (SCZ), and Bipolar Disorder (BD), when compared to healthy controls (about 200 post-mortem samples). Moreover, we performed the same analysis in the putamen of non-human primate Macaca Mulatta, lesioned with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Overall, our data indicated comparable Rhes mRNA levels in the brain of patients with SCZ and BD, and their respective healthy controls. In sharp contrast, the putamen of patients suffering from PD showed a significant 35% reduction of this transcript, compared to healthy subjects. Interestingly, in line with observations obtained in humans, we found 27% decrease in Rhes mRNA levels in the putamen of MPTP-treated primates. Based on the established inhibitory influence of Rhes on dopamine-related responses, we hypothesize that its striatal downregulation in PD patients and animal models of PD might represent an adaptive event of the dopaminergic system to functionally counteract the reduced nigrostriatal innervation.
Asunto(s)
Química Encefálica , Proteínas de Unión al GTP/metabolismo , Enfermedad de Parkinson/metabolismo , ARN Mensajero/análisis , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Anciano , Anciano de 80 o más Años , Animales , Trastorno Bipolar/metabolismo , Química Encefálica/efectos de los fármacos , Estudios de Casos y Controles , Femenino , Humanos , Macaca mulatta , Masculino , Persona de Mediana Edad , Putamen/química , Putamen/metabolismo , ARN Mensajero/metabolismo , Esquizofrenia/metabolismoRESUMEN
BACKGROUND: Molecular adaptations are believed to contribute to the mechanism of action of antipsychotic drugs (APDs). We attempted to establish common gene regulation patterns induced by chronic treatment with APDs. METHODS: Gene expression analysis was performed with the Affymetrix U34A array in the frontal cortex (FC) and the striatum of rats chronically treated with two concentrations of either clozapine or haloperidol. Key data were verified with real-time quantitative polymerase chain reaction. RESULTS: Many genes in the FC affected by APD-treatment contribute to similar functions. mRNAs coding for synaptic vesicle docking- and microtubule-associated proteins were upregulated; mRNAs for serine-threonine protein phosphatases were downregulated, whereas the serine-threonine kinases protein kinase A, protein kinase C, and calcium/calmodulin kinase II alpha and IV were upregulated, indicating increased potential for protein phosphorylation. In the striatum, altered gene expression was less focused on genes of particular function or location, and the high concentration of haloperidol had a different gene expression profile than any of the other APD treatments. CONCLUSION: We found an increase in the transcription of genes coding for proteins involved in synaptic plasticity and synaptic activity in the FC. We furthermore found that the gene expression profile of APDs is different between FC and striatum.
Asunto(s)
Antipsicóticos/farmacología , Lóbulo Frontal/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Animales , Análisis por Conglomerados , Cuerpo Estriado/efectos de los fármacos , Masculino , Microtúbulos/genética , Microtúbulos/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Terminales Presinápticos/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Vesículas Sinápticas/genética , Vesículas Sinápticas/metabolismoRESUMEN
The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the activity of the glutamate system and its receptors. Malfunctions of the glutamate system affect neuroplasticity and can cause neuronal toxicity. In schizophrenia, many glutamate-regulated processes seem to be perturbed. Abnormal neuronal development, abnormal synaptic plasticity, and neurodegeneration have been proposed to be causal or contributing factors in schizophrenia. Interestingly, it seems that the glutamate system is dysregulated and that N-methyl-D-aspartate receptors operate at reduced activity. Here we discuss how the molecular aspects of glutamate malfunction can explain some of the neuropathology observed in schizophrenia, and how the available treatment intervenes through the glutamate system.