RESUMEN
Stress can either strengthen coping strategies or enhance the risk of depression and anxiety. Synaptic plasticity is one of the key brain functions that can be affected by stress. We have previously shown that early-life stress in the form of maternal separation (MS) impairs functional synaptic plasticity in the medial prefrontal cortex (mPFC), i.e., long-term potentiation (LTP), in adolescent rats. It has been postulated that a previous experience of prolonged stress can modify the response to a subsequent acute stress challenge and influence coping strategies. Therefore, in the present study, we examined how previous MS experience influenced acute stress-induced changes in the LTP and expression of genes and proteins engaged in synaptic plasticity in the mPFC of adolescent rats. To mimic acute stress, we applied acute injections of corticosterone (CORT) and its vehicle (VEH). In control rats, acute CORT injection enhanced LTP in the mPFC. In contrast, MS rats generally exhibited an impairment of LTP that was not further affected by CORT. Moreover, for many studied parameters, such as induction of cFos and Arc mRNA and protein and activation of BDNF, GDNF and NCAM mRNA, MS rats showed diminished, vague or absent responses to acute VEH/CORT compared with those of control rats. These results suggest that previous early-life stress experiences may induce adaptive plasticity within the mPFC, which influences the response to acute stress challenge and coping strategies in adolescents. Depending on the specific environmental context, this phenomenon may lead to either future vulnerability or future resilience to stress-related psychopathologies.
Asunto(s)
Plasticidad Neuronal/fisiología , Corteza Prefrontal/crecimiento & desarrollo , Corteza Prefrontal/fisiopatología , Estrés Psicológico/fisiopatología , Animales , Corticosterona/administración & dosificación , Corticosterona/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Potenciación a Largo Plazo/fisiología , Masculino , Privación Materna , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas Wistar , Maduración Sexual , Técnicas de Cultivo de TejidosRESUMEN
In the present study, we investigated whether exposure to an enriched environment (EE) during adolescence might affect the behavioural dysfunction (sensorimotor gating deficit, memory and social interaction impairments) and neurochemical changes (GAD67 expression, histone methylation) induced by methylazoxymethanol (MAM) in the MAM-E17 rat model of schizophrenia. EE was introduced for 7 days in early adolescence (days 23-29), and behavioural and biochemical studies were performed on adult rats at postnatal day 70. The results showed that exposure to EE prevented the development of adult behavioural deficits induced by prenatal MAM administration. EE also prevented the decrease in GAD67 mRNA and protein levels induced by MAM in the medial prefrontal cortex (mPFC). Moreover, EE inhibited the reductions in the amount of Gad1 bound to H3K4me3 and in the total H3K4me3 protein level induced by prenatal MAM administration in the adult mPFC. However, there was no effect of EE on behaviour or levels of the various neurochemical markers in adult rats prenatally treated with vehicle. Thus, these results indicate that EE exposure during early adolescence may inhibit the development of schizophrenia related symptoms through epigenetic mechanisms that regulate the expression of genes (e.g., Gad1) that are impaired in schizophrenia.
Asunto(s)
Ambiente , Vivienda para Animales , Esquizofrenia/prevención & control , Animales , Modelos Animales de Enfermedad , Histonas/genética , Histonas/metabolismo , Masculino , Acetato de Metilazoximetanol/análogos & derivados , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Distribución Aleatoria , Ratas Wistar , Esquizofrenia/metabolismo , Esquizofrenia/patología , Psicología del Esquizofrénico , Maduración Sexual , Metiltransferasa de ADN de Sitio Específico (Adenina Especifica)RESUMEN
During adolescence, many neural systems, including the dopamine system, undergo essential remodeling and maturation. It is well known that early-life stress (ELS) increases the risk for many psychopathologies during adolescence and adulthood. It is hypothesized that ELS interferes with the maturation of the dopamine system. There is a sex bias in the prevalence of stress-related mental disorders. Information regarding the effects of ELS on brain functioning in females is very limited. In the current study, maternal separation (MS) procedures were carried out to study the effects of ELS on dopamine system functioning in adolescent female rats. Our study showed that MS increased the density of tyrosine hydroxylase immunoreactive fibers in the prelimbic cortex (PLC) and nucleus accumbens (Acb). These changes were accompanied by a decrease in the level of D5 receptor mRNA and an increase in D2 receptor mRNA expression in the PLC of MS females. Conversely, D1 and D5 receptor mRNA levels were augmented in the caudate putamen (CPu), while the expression of the D3 dopamine receptor transcript was reduced in MS females. Additionally, in the Acb, MS elicited a decrease in D2 receptor mRNA expression. At the behavioral level, MS increased apomorphine-induced locomotion; however, it did not change locomotor responses to selective D1/D5 receptor agonist and attenuated D2/D3 receptor agonist-triggered locomotion. Moreover, MS decreased D1/D5 receptor agonist-induced grooming behavior. These results indicate that ELS disrupts dopamine receptor function in the PLC and basal ganglia during adolescence in females and may predispose them to psychopathologies during adolescence and adulthood.
Asunto(s)
Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Dopamina/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Estrés Psicológico/patología , Animales , Animales Recién Nacidos , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Dopaminérgicos/farmacología , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Aseo Animal/efectos de los fármacos , Aseo Animal/fisiología , Locomoción/efectos de los fármacos , Locomoción/fisiología , Privación Materna , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Estrés Psicológico/etiología , Estrés Psicológico/fisiopatología , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
BACKGROUND: Epidemiological data have indicated that memory impairment is observed during adolescence in groups at high risk for schizophrenia and might precede the appearance of schizophrenia symptoms in adulthood. METHODS: In the present study, we used a neurodevelopmental model of schizophrenia based on the postnatal blockade of N-methyl-d-aspartate (NMDA) receptors in rats to investigate fear memory in adolescence and adulthood. The rats were treated with increasing doses of CGP 37849 (CGP), a competitive antagonist of the NMDA receptor (1.25mg/kg on days 1, 3, 6, 9; 2.5mg/kg on days 12, 15, 18 and 5mg/kg on day 21). Fear memory was analysed in delay and trace fear conditioning. Sensorimotor gating deficit, which is another cognitive symptom of schizophrenia, was also determined in adolescent and adult CGP-treated rats. RESULTS: Postnatal CGP administration disrupted cue- and context-dependent fear memory in adolescent rats in both delay and trace conditioning. In contrast, CGP administration evoked impairment only in cue-dependent fear memory in rats exposed to trace but not delay fear conditioning. The postnatal blockade of NMDA receptors induced sensorimotor gating deficits in adult rats but not in adolescent rats. CONCLUSIONS: The postnatal blockade of NMDA receptors induced fear memory impairment in adolescent rats before the onset of neurobehavioral deficits associated with schizophrenia.
Asunto(s)
Modelos Animales de Enfermedad , Antagonistas de Aminoácidos Excitadores/farmacología , Miedo/efectos de los fármacos , Memoria/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Esquizofrenia/inducido químicamente , Animales , Animales Recién Nacidos , Antagonistas de Aminoácidos Excitadores/toxicidad , Miedo/fisiología , Miedo/psicología , Femenino , Masculino , Memoria/fisiología , Embarazo , Inhibición Prepulso/efectos de los fármacos , Inhibición Prepulso/fisiología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/fisiología , Psicología del EsquizofrénicoRESUMEN
BACKGROUND: Evidence indicates that the disruption of epigenetic processes might play an important role in the development of schizophrenia symptoms. The present study investigated the role of histone acetylation in the development of sensorimotor gating deficits in a neurodevelopmental model of schizophrenia based on prenatal administration of methylazoxymethanol (MAM) at embryonic day 17. METHODS: Valproic acid (VPA), an inhibitor of class I histone deacetylases, was administered (250 mg/kg, twice a day for 7 consecutive days) in early adolescence (23rd-29th day) or early adulthood (63rd-69th day) to rats. The effect of VPA treatment on the sensorimotor gating deficits induced by prenatal MAM administration was analyzed in adult rats at postnatal day 70 (P70). In addition, the effects of VPA administration (at the same doses) on MAM-induced changes in the levels of histone H3 acetylation at lysine 9 (H3K9ac) and histone deacetylase 2 (HDAC2) in the medial prefrontal cortex (mPFC) were determined at P70 using Western blot. RESULTS: VPA administration in either adolescence or early adulthood prevented the sensorimotor gating deficits induced by MAM. However, VPA administration in early adolescence or early adulthood did not alter H3K9ac levels induced by MAM. In contrast, VPA administration in either adolescence or adulthood prevented the increase in HDAC2 level evoked by MAM. CONCLUSIONS: Prenatal MAM administration impaired histone acetylation in the mPFC, which might be involved in the development of some of the neurobehavioral deficits (i.e., sensorimotor gating deficits) associated with schizophrenia. Blockade of HDAC2 might prevent the disruption of sensorimotor gating in adulthood.
Asunto(s)
Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Histona Desacetilasa 2/biosíntesis , Esquizofrenia/fisiopatología , Filtrado Sensorial/efectos de los fármacos , Ácido Valproico/farmacología , Acetilación/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Femenino , Histonas/metabolismo , Masculino , Acetato de Metilazoximetanol/análogos & derivados , Corteza Prefrontal/metabolismo , Ratas , Esquizofrenia/inducido químicamente , Esquizofrenia/enzimología , Filtrado Sensorial/fisiologíaRESUMEN
Currently, much attention is focused on the influence of mitochondrial disturbances at the onset of depression. The goal of this study was to investigate the impact of prenatal stress (an animal model of depression) on the mitochondrial biogenesis proteins and mitoproteome profile in the frontal cortex and hippocampus of adult 3-month-old male rats following a prenatal stress procedure. Our results show that rats that were exposed to prenatal stress stimuli displayed depression-like behaviors based on the sucrose preference and elevated plus maze tests. It has been found that the level of the PGC-1α protein was reduced in the frontal cortex and hippocampus of the adult offspring after the prenatal stress procedure. Moreover, in the frontal cortex, the level of the pro-apoptotic protein Bax was up-regulated. Two-dimensional electrophoresis coupled with mass spectrometry showed the statistically significant down-regulation of the mitochondrial ribosomal protein L12 (Mrpl12) and mitochondrial NADH dehydrogenase [ubiquinone] flavoprotein 2 (NDUFV2) as well as the up-regulation of the Tubulin Polymerization Promoting Proteins (Tppp/p25) in the frontal cortex. In contrast, in the hippocampus, the mitochondrial pyruvate dehydrogenase E1 component subunit beta, the voltage-dependent anion-selective channel protein 2 (VDAC2), and the GTP-binding nuclear protein RAN (RAN) were down-regulated and the expression of phosphatidylethanolamine-binding protein 1 (PEBP-1) was enhanced. These findings provide new evidence that stress during pregnancy may lead not only to behavioral deficits, but also to disturbances in the brain mitoproteome profile in adult rat offspring.
Asunto(s)
Lóbulo Frontal/metabolismo , Hipocampo/metabolismo , Proteínas Mitocondriales/biosíntesis , Efectos Tardíos de la Exposición Prenatal/psicología , Estrés Psicológico/psicología , Animales , Ansiedad/psicología , Depresión/psicología , Femenino , Preferencias Alimentarias , Masculino , Mitocondrias/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Embarazo , Proteómica , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Factores de Transcripción/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Clinical studies have suggested that early-life stress (ELS) increases the risk of psychopathologies that are strongly associated with dysfunction of dopaminergic neurotransmission. Thus, ELS may interfere with the development and maturation of the dopaminergic system; however, the mechanisms involved in such interference are poorly understood. In the present study, we investigated the effect of ELS on the survival of specific populations of neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) during postnatal development. First, we injected bromodeoxyuridine (BrdU) into pregnant rat dams on embryonic days 12, 13 and 14 to permanently label midbrain neurons. Then, after birth, the dams and litters were subjected to a maternal separation (MS) procedure to model ELS conditions. The number of BrdU+ neurons and the total number of neurons (cresyl violet+, CV+) were estimated in both male and female juvenile, adolescent, and adult rats. Moreover, sucrose preference and anxiety-like behaviors were studied during adulthood. We found that MS permanently increased the number of BrdU+ and CV+ neurons in the VTA of males. In the SNc, a temporary increase in the number of BrdU+ neurons was observed in juvenile MS males; however, only adult MS males displayed an increase in the number of CV+ neurons. Immunofluorescence analysis implied that MS affected the fate of non-dopaminergic neurons. MS males displayed anxiolytic-like behavior and an increase in sucrose preference. These results suggest that ELS induces distinct dysregulation in the midbrain circuitry of males, which may lead to sex-specific psychopathology of the reward system.
Asunto(s)
Ansiedad de Separación/etiología , Privación Materna , Mesencéfalo/patología , Neuronas/patología , Recompensa , Caracteres Sexuales , Estrés Psicológico , Adaptación Ocular , Factores de Edad , Animales , Bromodesoxiuridina/metabolismo , Recuento de Células , Femenino , Preferencias Alimentarias , Masculino , Mesencéfalo/crecimiento & desarrollo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Embarazo , Ratas , Ratas Wistar , Estrés Psicológico/complicaciones , Estrés Psicológico/patología , Estrés Psicológico/psicología , Sacarosa/administración & dosificación , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Several lines of evidence suggest that the dysregulation of the immune system is an important factor in the development of depression. Microglia are the resident macrophages of the central nervous system and a key player in innate immunity of the brain. We hypothesized that prenatal stress (an animal model of depression) as a priming factor could affect microglial cells and might lead to depressive-like disturbances in adult male rat offspring. We investigated the behavioral changes (sucrose preference test, Porsolt test), the expression of C1q and CD40 mRNA and the level of microglia (Iba1 positive) in 3-month-old control and prenatally stressed male offspring rats. In addition, we characterized the morphological and biochemical parameters of potentially harmful (NO, iNOS, IL-1ß, IL-18, IL-6, TNF-α, CCL2, CXCL12, CCR2, CXCR4) and beneficial (insulin-like growth factor-1 (IGF-1), brain derived neurotrophic factor (BDNF)) phenotypes in cultures of microglia obtained from the cortices of 1-2 days old control and prenatally stressed pups. The adult prenatally stressed rats showed behavioral (anhedonic- and depression-like) disturbances, enhanced expression of microglial activation markers and an increased number of Iba1-immunopositive cells in the hippocampus and frontal cortex. The morphology of glia was altered in cultures from prenatally stressed rats, as demonstrated by immunofluorescence microscopy. Moreover, in these cultures, we observed enhanced expression of CD40 and MHC II and release of pro-inflammatory cytokines, including IL-1ß, IL-18, TNF-α and IL-6. Prenatal stress significantly up-regulated levels of the chemokines CCL2, CXCL12 and altered expression of their receptors, CCR2 and CXCR4 while IGF-1 production was suppressed in cultures of microglia from prenatally stressed rats. Our results suggest that prenatal stress may lead to excessive microglia activation and contribute to the behavioral changes observed in depression in adulthood.
RESUMEN
Neuroligins are postsynaptic adhesion molecules that are involved in the regulation of synapse organisation and function. Four neuroligin proteins have been identified (neuroligin 1, 2, 3, 4), which are differentially enriched in the postsynaptic specialisation of synapses. Neuroligin 1 is localised on excitatory (glutamatergic) synapses, whereas neuroligin 2 is located on inhibitory (GABAergic/glycinergic) synapses. Neuroligin 3 and 4 are present on both types of synapses. Recent data indicate that neuroligins are involved in synapse maturation and specification. Because of their synaptic localisation and function, neuroligins control the balance between excitatory and inhibitory synapses. Animal studies with neuroligin transgenic mice showed the involvement of neuroligin 1 in memory formation, and neuroligin 2, 3 or 4 in social behaviour. Interestingly, genetic analysis of humans showed a mutation in the neuroligin 2 gene in schizophrenic patients, while mutations in neuroligin 3 or 4 genes were found in autism.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/metabolismo , Trastornos Mentales/fisiopatología , Sinapsis/metabolismo , Animales , Moléculas de Adhesión Celular Neuronal/genética , Humanos , Memoria/fisiología , Ratones , Ratones Transgénicos , Mutación , Conducta SocialRESUMEN
Adolescence is a developmental period characterized by extensive morphological and functional remodeling of the brain. The processes of brain maturation during this period may unmask malfunctions that originate earlier in life as a consequence of early-life stress (ELS). This is associated with the emergence of many psychopathologies during adolescence, particularly affective spectrum disorders. In the present study, we applied a maternal separation (MS) procedure (3h/day, on postnatal days 1-14) as a model of ELS to examine its effects on the acquisition, expression and extinction of fear memories in adolescent rats. Additionally, we studied the persistence of these memories into adulthood. We found that MS decreased the expression of both contextual (CFC) and auditory (AFC) fear conditioning in adolescent rats. Besides, MS had no impact on the acquisition of extinction learning. During the recall of extinction MS animals both, those previously subjected and not subjected to the extinction session, exhibited equally low levels of freezing. In adulthood, the MS animals (conditioned during adolescence) still displayed impairments in the expression of AFC (only in males) and CFC. Furthermore, the MS procedure had also an impact on the expression of CFC (but not AFC) after retraining in adulthood. Our findings imply that ELS may permanently affect fear learning and memory. The results also support the hypothesis that, depending on individual predispositions and further experiences, ELS may either lead to a resilience or a vulnerability to early- and late-onsets psychopathologies.
Asunto(s)
Condicionamiento Clásico/fisiología , Miedo/psicología , Privación Materna , Memoria/fisiología , Estimulación Acústica/efectos adversos , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Electrochoque/efectos adversos , Extinción Psicológica , Femenino , Reacción Cataléptica de Congelación/fisiología , Masculino , Umbral del Dolor/fisiología , Ratas , Ratas Wistar , Factores SexualesRESUMEN
Several findings have indicated that schizophrenia may be connected with the impaired epigenetic regulation of gene transcription. The present study investigated the epigenetic modifications connected with histone H3 methylation at lysine (K)4 and K9 in the medial prefrontal cortex (mPFC) in a neurodevelopmental model of schizophrenia based on prenatal administration of methylazoxymethanol (MAM) at embryonic day 17, which impairs the sensorimotor gating process in adult but not adolescent animals. The effect of MAM was determined at different postnatal ages, pre-puberty (P15, P30 and P45) and post-puberty (P60 and P70), using western blot analyses. MAM treatment altered the levels of H3K9me2 before puberty. H3K9me2 was decreased at P15 and P45 but was increased at P30. In contrast, H3K4me3 was noticeably decreased in adult rats. Immunofluorescence experiments revealed that H3K9me2 protein levels were increased in neuronal cells at P30 and that H3K4me3 levels were decreased in astrocytes at P60 after MAM administration. Decreases in the methyltransferase ASH2L protein levels at P45, P60 and P70 were also observed, while the protein levels of the methyltransferase G9a did not change. In addition, levels of the demethylases LSD1 and JARID1c were analysed after MAM administration. LSD1 protein levels were increased at P15 but decreased at P30. JARID1c protein levels were increased in the MAM-treated animals at P60. Decreased Gad1 mRNA levels were found in adult MAM-treated animals, similar to alternation observed in schizophrenia. The present study indicates that prenatal MAM administration evokes changes in the methylation patterns of histone H3 during postnatal life.
Asunto(s)
Histonas/metabolismo , Acetato de Metilazoximetanol/análogos & derivados , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/crecimiento & desarrollo , Teratógenos/farmacología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Peso Corporal/efectos de los fármacos , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Inhibidores Enzimáticos/farmacología , Glutamato Descarboxilasa/metabolismo , Histona Demetilasas/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Masculino , Metilación/efectos de los fármacos , Acetato de Metilazoximetanol/farmacología , Metiltransferasas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oxidorreductasas N-Desmetilantes/metabolismo , Corteza Prefrontal/anatomía & histología , Corteza Prefrontal/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Filtrado Sensorial/efectos de los fármacos , Ácido Valproico/farmacologíaRESUMEN
Early life experiences are crucial factors that shape brain development and function due to their ability to induce structural and functional plasticity. Among these experiences, early-life stress (ELS) is known to interfere with brain development and maturation, increasing the risk of future psychopathologies, including depression, anxiety, and personality disorders. Moreover, ELS may contribute to the emergence of these psychopathologies during adolescence. In this present study, we investigated the effects of ELS, in the form of maternal separation (MS), on the structural and functional plasticity of the medial prefrontal cortex (mPFC) and anxiety-like behavior in adolescent male rats. We found that the MS procedure resulted in disturbances in mother-pup interactions that lasted until weaning and were most strongly demonstrated by increases in nursing behavior. Moreover, MS caused atrophy of the basal dendritic tree and reduced spine density on both the apical and basal dendrites in layer II/III pyramidal neurons of the mPFC. The structural changes were accompanied by an impairment of long-term potentiation processes and increased expression of key proteins, specifically glutamate receptor 1, glutamate receptor 2, postsynaptic density protein 95, αCa(2+) /calmodulin-dependent protein kinase II and αCa(2+)/calmodulin-dependent protein kinase II phosphorylated at residue Thr305, that are engaged in long-term potentiation induction and maintenance in the mPFC. We also found that the MS animals were more anxious in the light/dark exploration test. The results of this study indicate that ELS has a significant impact on the structural and functional plasticity of the mPFC in adolescents. ELS-induced adaptive plasticity may underlie the pathomechanisms of some early-onset psychopathologies observed in adolescents.
Asunto(s)
Potenciación a Largo Plazo , Privación Materna , Corteza Prefrontal/fisiología , Estrés Psicológico/fisiopatología , Factores de Edad , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Espinas Dendríticas/ultraestructura , Homólogo 4 de la Proteína Discs Large , Conducta Exploratoria , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Conducta Materna , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Corteza Prefrontal/citología , Células Piramidales/metabolismo , Células Piramidales/fisiología , Ratas , Ratas Wistar , Receptores AMPA/genética , Receptores AMPA/metabolismo , Estrés Psicológico/etiología , Estrés Psicológico/patologíaRESUMEN
Although anxiety and mood disorders (MDs) are the most common mental diseases, the etiologies and mechanisms of these psychopathologies are still a matter of debate. The medial prefrontal cortex (mPFC) is a brain structure that is strongly implicated in the pathophysiology of these disorders. A growing number of epidemiological and clinical studies show that early-life stress (ELS) during the critical period of brain development may increase the risk for anxiety and MDs. Neuroimaging analyses in humans and numerous reports from animal models clearly demonstrate that ELS affects behaviors that are dependent on the mPFC, as well as neuronal activity and synaptic plasticity within the mPFC. The mechanisms engaged in ELS-induced changes in mPFC function involve alterations in the developmental trajectory of the mPFC and may be responsible for the emergence of both early-onset (during childhood and adolescence) and adulthood-onset anxiety and MDs. ELS-evoked changes in mPFC synaptic plasticity may constitute an example of metaplasticity. ELS may program brain functions by affecting glucocorticoid levels. On the molecular level, ELS-induced programming is registered by epigenetic mechanisms, such as changes in DNA methylation pattern, histone acetylation and microRNA expression. Vulnerability and resilience to ELS-related anxiety and MDs depend on the interaction between individual genetic predispositions, early-life experiences and later-life environment. In conclusion, ELS may constitute a significant etiological factor for anxiety and MDs, whereas animal models of ELS are helpful tools for understanding the pathomechanisms of these disorders.
Asunto(s)
Ansiedad/fisiopatología , Trastornos del Humor/fisiopatología , Corteza Prefrontal/fisiopatología , Estrés Psicológico/fisiopatología , Animales , Ansiedad/genética , Epigénesis Genética/genética , Humanos , Trastornos del Humor/genética , Estrés Psicológico/genéticaRESUMEN
Recently, it has been proposed that abnormalities in neuronal structural plasticity may underlie the pathogenesis of major depression, resulting in changes in the volume of specific brain regions, including the hippocampus (HIP), the prefrontal cortex (PC), and the amygdala (AMY), as well as the morphology of individual neurons in these brain regions. In the present survey, we compile the data regarding the involvement of the neural cell adhesion molecule (NCAM) protein and its polysialylated form (PSA-NCAM) in the pathogenesis of depression and the mechanism of action of antidepressant drugs (ADDs). Elevated expression of PSA-NCAM may reflect neuroplastic changes, whereas decreased expression implies a rigidification of neuronal morphology and an impedance of dynamic changes in synaptic structure. Special emphasis is placed on the clinical data, genetic models, and the effects of ADDs on NCAM/PSA-NCAM expression in the brain regions in which these proteins are constitutively expressed and neurogenesis is not a major factor; this emphasis is necessary to prevent cell proliferation and neurogenesis from obscuring the issue of brain plasticity.
Asunto(s)
Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Depresión/metabolismo , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Ácidos Siálicos/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , HumanosRESUMEN
BACKGROUND: The present study investigated whether MK-801, when given in doses that cause psychomimetic effects in rats, could alter the phosphorylation of histone 3 (H3) at serine 10 (H3S10p) and the acetylation of H3 at lysine 14 (H3K14ac) in the medial prefrontal cortex (mPFC). These posttranslational modifications of H3 promote chromatin relaxation and increase the probability of gene expression. METHODS: Stereological counting, immunoblot analysis and confocal laser scanning microscopy. RESULTS: Treatment with MK-801 (0.4 mg/kg) evoked a time-dependent increase in the number of H3S10p positive nuclei in both the II/III and V/VI layers of the mPFC, reaching the peak of activation 30 min after injection. MK-801 treatment (0.4 mg/kg) failed to alter H3K14ac. These effects were confirmed by immunoblot analysis on tissue samples from the mPFC. Analysis of cortical cells expressing H3S10p positive nuclei revealed that constitutive and MK-801-induced expression of H3S10p was observed only in neurons and not in glia cells (H3S10p colocalized with NeuN but not with S-100ß). Moreover, it has been found that H3S10p is exclusively present in pyramidal (glutamate-positive) but not in cortical GABA-ergic interneurons (GABA-positive). The effects of MK-801 can be attenuated or blocked by the neuroleptic drug risperidone. In the cortical layer II/III, risperidone was effective at doses of 0.2 and 1 mg/kg, while it was only active at a dose of 1 mg/kg in the V/VI layer. Again, these stereological data were confirmed by immunoblot analysis. CONCLUSIONS: Our results indicate that MK-801 may increase the transcriptional activity of mPFC via the activation of the epigenetic program associated with H3S10p phosphorylation during the course of experimental psychosis.
Asunto(s)
Maleato de Dizocilpina/toxicidad , Antagonistas de Aminoácidos Excitadores/toxicidad , Histonas/metabolismo , Corteza Prefrontal/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Psicosis Inducidas por Sustancias/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Acetilación , Animales , Antipsicóticos/farmacología , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Lisina , Masculino , Fenotipo , Fosforilación , Corteza Prefrontal/metabolismo , Psicosis Inducidas por Sustancias/genética , Psicosis Inducidas por Sustancias/prevención & control , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Risperidona/farmacología , Serina , Factores de TiempoRESUMEN
BACKGROUND: Prenatal immune system disturbances have been postulated to play an important role in pathogenesis of schizophrenia and related disorders. In the present study, we sought to answer the question whether behavioral changes in the neurodevelopmental model of schizophrenia in rats are accompanied by alterations in proliferative activity of splenocytes and pro- and anti-inflammatory cytokine levels. Furthermore, the effects of two antipsychotic drugs on these parameters were determined. METHODS: Lipopolysaccharide (LPS) was administered subcutaneously to pregnant dams at a dose of 1 mg/kg every second day from the 7(th) day of pregnancy till delivery. Age-dependent behavioral and immunological changes were studied when control and prenatally LPS-pretreated offspring male rats were 30 and 90 days old. Chlorpromazine (10 mg/kg ip) or clozapine (10 mg/kg ip) was administered chronically (21 days) after behavioral verification to 3 months old offspring males. Changes in sensorimotor gating (prepulse inhibition, PPI), mitogen-induced proliferative activity of splenocytes ([(3)H]-thymidine incorporation) and cytokine levels (ELISA) were measured. RESULTS: Prenatally LPS-pretreated rats showed PPI deficit only at 90 but not at 30 days of age, whereas an enhancement of mitogen-stimulated proliferative activity of splenocytes was observed in both time points. Additionally, the level of proinflammatory cytokines (IL-1ß, IL-2, IL-6, TNF-α) in prenatally LPS-pretreated rats was enhanced when they were 30 days old and remained elevated in 90 days old offspring. No changes in IL-10 level were observed. Chronic administration of chlorpromazine or clozapine reduced the deficit in PPI deficit in prenatally LPS-treated rats. In the used model, chlorpromazine normalized both T and B lymphocyte proliferation, whereas clozapine B lymphocyte activity only. Moreover, both antipsychotics modulated the enhanced levels of IL-1ß, IL-2 and TNF-α in the offspring of LPS-treated mothers. CONCLUSIONS: This study indicates that in LPS-evoked model of schizophrenia, peripheral immunological changes are long-lasting and precede behavioral deficit. The disturbances in T cell-mediated immunity as well as cytokine production were attenuated by antipsychotic drug administration.
Asunto(s)
Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Clorpromazina/farmacología , Clozapina/farmacología , Lipopolisacáridos/toxicidad , Exposición Materna , Efectos Tardíos de la Exposición Prenatal , Esquizofrenia/tratamiento farmacológico , Bazo/efectos de los fármacos , Factores de Edad , Envejecimiento , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/sangre , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Esquema de Medicación , Ensayo de Inmunoadsorción Enzimática , Femenino , Mediadores de Inflamación/sangre , Inyecciones Subcutáneas , Lipopolisacáridos/administración & dosificación , Activación de Linfocitos/efectos de los fármacos , Masculino , Embarazo , Ratas , Ratas Wistar , Reflejo de Sobresalto/efectos de los fármacos , Esquizofrenia/inducido químicamente , Esquizofrenia/inmunología , Psicología del Esquizofrénico , Filtrado Sensorial/efectos de los fármacos , Bazo/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Factores de TiempoRESUMEN
Recent data indicate that a significant number of schizophrenic patients are hypercortisolemic and that glucocorticoids are involved in the pathogenesis of schizophrenia. The aim of the present study was to evaluate whether behavioural schizophrenia-like changes in the lipopolysaccharide (LPS)-induced neurodevelopmental model of this brain disorder are associated with alterations in the level of plasma corticosterone, the concentration of glucocorticoid receptors and the amount of the immunophilin FKBP51, the glucocorticoid receptor co-chaperone, in the hippocampus and frontal cortex. We found that the adult offspring of prenatally LPS-treated rats showed a deficit in prepulse inhibition (PPI), an enhancement of amphetamine-induced locomotor activity, an elevated plasma level of corticosterone and a decrease in both the glucocorticoid receptor level in the hippocampus and the FKBP51 concentration in the frontal cortex. Most of these changes were reversed by the atypical antipsychotic drug clozapine, whereas chlorpromazine had no effect on PPI but attenuated the amphetamine-induced hyperactivity and normalised the hippocampal level of glucocorticoid receptors. The changes in the level of plasma corticosterone and cortical FKBP51 were attenuated by chlorpromazine in female offspring only. This study supports the hypothesis of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in schizophrenia and suggests that this hyperactivity results from a decrease in the hippocampal glucocorticoid receptor level and a decrease in FKBP51 in the frontal cortex.
Asunto(s)
Antipsicóticos/farmacología , Clozapina/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Esquizofrenia/metabolismo , Anfetamina/farmacología , Animales , Clorpromazina/farmacología , Corticosterona/sangre , Femenino , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Lipopolisacáridos/farmacología , Masculino , Exposición Materna , Intercambio Materno-Fetal , Sistema Hipófiso-Suprarrenal/fisiopatología , Embarazo , Ratas , Ratas Wistar , Receptores de Glucocorticoides/metabolismo , Esquizofrenia/fisiopatología , Proteínas de Unión a Tacrolimus/metabolismoRESUMEN
In the present study, detailed information is presented on the hetero-dimerization of the serotonin 5-HT(2A) receptor and the dopamine D(2) receptor. Biophysical approaches (fluorescence spectroscopy as well as fluorescence lifetime microscopy) were used to determine the degree of fluorescence resonance energy transfer (FRET) between cyan and yellow fluorescent protein labeled receptor variants co-expressed in human embryonic kidney 293 cells (HEK293). Recorded data demonstrate the existence of energy transfer between the wild-type forms of 5-HT(2A)R and D(2)R, pointing toward the formation of hetero-5-HT(2A)R/D(2)R dimers and homo-5-HT(2A)R/5-HT(2A)R dimers. Moreover, the present study investigates the role of specific motifs (one containing adjacent arginine residues (217RRRRKR222) in the third intracellular loop (ic3) of D(2)R, and the other consisting of acidic glutamate residues (454EE455) in the C-tail of (5-HT(2A)R) in the formation of noncovalent complexes between these receptors. Our results suggest that these regions of 5-HT(2A)R and D(2)R may be involved in the interaction between these two proteins. On the other hand, the above-mentioned motifs do not play an important role in the homo-dimerization of these receptors. Furthermore, we estimated the influence of specific receptor ligands on the dimerization processes. Agonists (DOI and quinpirole) and antagonists (ketanserin and butaclamol) cause different effects on FRET efficiency depending on whether homo- or hetero-complexes are present. These data may have therapeutic implications, since (using the immunofluorescence double labeling protocols) the co-localization of these two receptors was demonstrated in the medial prefrontal cortex and pars reticulate of the substantia nigra of the rat brain.
Asunto(s)
Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Dopamina D2/metabolismo , Línea Celular , Dimerización , Transferencia Resonante de Energía de Fluorescencia , Humanos , Microscopía Confocal , Ensayo de Unión RadioliganteRESUMEN
Stressful experiences in the early stages of life can influence brain development and maturation, and they can also increase the risk for some psychiatric disorders; however, the specific mechanisms of this effect are still poorly understood. Neural cell adhesion molecules (NCAM 120, 140, 180 kDa) are known to play an important role in normal brain development and synaptic plasticity. Therefore, we decided to investigate whether maternal separation (MS) in rats, a paradigm which models an early life stress, has any impact on the expression of NCAM proteins in the juvenile, adolescent and adult brains of both male and female rats. Specifically, we focused our efforts on the brain regions associated with dopaminergic neurotransmission. In juvenile rats, MS decreased the levels of NCAM-140 in the substantia nigra (SN) of females and NCAM-180 in the ventral tegmental area of males. During adolescence, a reduction in NCAM-180 levels in the SN and medial prefrontal cortex (mPFC) of MS females was revealed. Finally, in adulthood, a decrease in NCAM-180 expression was observed in the mPFC of MS males. The results that we obtained indicate that early life stress can affect maturation and NCAM-driven plasticity in dopaminergic brain areas at different stages of ontogenesis and with a sex-specific manner.
Asunto(s)
Dopamina/metabolismo , Privación Materna , Moléculas de Adhesión de Célula Nerviosa/biosíntesis , Corteza Prefrontal/metabolismo , Sustancia Negra/metabolismo , Área Tegmental Ventral/metabolismo , Animales , Femenino , Masculino , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Plasticidad Neuronal , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Corteza Prefrontal/citología , Ratas , Ratas Wistar , Estrés Psicológico , Sustancia Negra/citología , Transmisión Sináptica , Área Tegmental Ventral/citologíaRESUMEN
The present study investigated the potential role of the extracellular signal-regulated kinase (ERK) pathway in the alternation of polysialylated neural cell adhesion molecule (PSA-NCAM) expression and proliferation rates in the dentate gyrus (DG) evoked by activation of the CB1 receptor. When given at a dose of 0.1 mg/kg, the CB1 receptor agonist, 3-(1,1-dimethylheptyl)-11-hydroxy-Delta(8)-tetrahydrocannabinol (HU-210), increased the levels of the phosphorylated forms of ERK (pERK1 and pERK2) in the hippocampus when measured 30 min after injection. This HU-210-induced effect was inhibited by alpha-{amino[(4-aminophenyl)thio]methylene}-2-(trifluoromethyl) benzeneacetonitrile (SL327, 30 mg/kg) - an inhibitor of mitogen-activated protein kinase kinase (MEK1/2), the upstream kinase of ERK - given 1 h before HU-210 administration. Additionally, SL327 alone significantly attenuated the basal level of both pERK1 and pERK2. HU-210 (0.1 mg/kg) decreased the number of PSA-NCAM-immunoreactive (IR) cells but did not affect the rate of proliferation, which was analyzed as the number of Ki-67-IR cells measured in the DG 2 days after HU-210 administration. The data indicated that SL327 (30 mg/kg) alone decreased the number of PSA-NCAM-IR cells 2 days after treatment. Joint administration of SL327 and HU-210 decreased the number of PSA-NCAM cells more robustly than did the administration of either alone. In addition, SL327 did not decrease the number of Ki-67-IR cells, while pretreatment with SL327 1 h before HU-210 administration did. These results suggest that stimulation of the ERK cascade caused by CB1 receptor activation is not involved in hippocampal plasticity governed by PSA-NCAM expression.