RESUMO
The brain-derived neurotrophic factor (BDNF) is a major proliferative agent in the nervous system. Both BDNF-deficiency and perinatal hypoxia represent genetic/environmental risk factors for schizophrenia. Moreover, a decreased BDNF response to birth hypoxia was associated with the disease. BDNF expression is influenced by neuronal activity and environmental conditions such as hypoxia. Thus, it may partake in neuroprotective and reparative mechanisms in acute or chronic neuronal insults. However, the interaction of hypoxia and BDNF is insufficiently understood and the behavioral outcome unknown. Therefore, we conducted a battery of behavioral tests in a classical model of chronic early postnatal mild hypoxia (10% O2), known to significantly impair brain development, in BDNF-deficient mice. We found selective deficits in measures associated with sensorimotor gating, namely enhanced acoustic startle response (ASR) and reduced prepulse inhibition (PPI) of ASR in BDNF-deficient mice. Unexpectedly, the alterations of sensorimotor gating were caused only by BDNF-deficiency alone, whereas hypoxia failed to evoke severe deficits and even leads to a milder phenotype in BDNF-deficient mice. As deficits in sensorimotor gating are present in schizophrenia and animal models of the disease, our results are of relevance regarding the involvement of BDNF in its pathogenesis. On the other hand, they suggest that the effect of perinatal hypoxia on long-term brain abnormalities is complex, ranging from protective to deleterious actions, and may critically depend on the degree of hypoxia. Therefore, future studies may refine existing hypoxia protocols to better understand neurodevelopmental consequences associated with schizophrenia.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/deficiência , Hipóxia/fisiopatologia , Inibição Pré-Pulso/fisiologia , Esquizofrenia/fisiopatologia , Filtro Sensorial/fisiologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
INTRODUCTION: Inflammatory processes play an important and complex role in the pathophysiology of major depressive disorder (MDD), but, so far, no specific investigation of chemokines exists. METHODS: In this study, we investigated the changes of plasma chemokine levels (eotaxin-1, eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1ß, and TARC) in 47 MDD patients before (PRE) and after 1 and 6 weeks of pharmacological treatment (POST1 and POST6) in relation to the response to antidepressive therapy. We hypothesized that the direction of alterations in levels of chemokines would significantly differ between the 2 groups, responders and nonresponders. RESULTS: Among the investigated chemokines, only the level of macrophage-derived chemokine (MDC) changed significantly in relation to therapy response. MDC levels were significantly elevated in the responder group at POST6. DISCUSSION: MDC is a constitutively expressed chemokine involved in the pathophysiology of infectious and neoplastic diseases. This is the first study providing valuable hints that MDC might serve as a marker of pharmacological therapy response in MDD.
Assuntos
Antidepressivos/uso terapêutico , Biomarcadores/sangue , Quimiocina CCL22/sangue , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Adolescente , Adulto , Resistência a Medicamentos/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Adolescence is characterized by important molecular and anatomical changes with relevance for the maturation of brain circuitry and cognitive function. This time period is of critical importance in the emergence of several neuropsychiatric disorders accompanied by cognitive impairment, such as affective disorders and schizophrenia. The molecular mechanisms underlying these changes at neuronal level during this specific developmental stage remains however poorly understood. GluA1-containing AMPA receptors, which are located predominantly on hippocampal neurons, are the primary molecular determinants of synaptic plasticity. We investigated here the consequences of the inducible deletion of GluA1 AMPA receptors in glutamatergic neurons during late adolescence. We generated mutant mice with a tamoxifen-inducible deletion of GluA1 under the control of the CamKII promoter for temporally and spatially restricted gene manipulation. GluA1 ablation during late adolescence induced cognitive impairments, but also marked hyperlocomotion and sensorimotor gating deficits. Unlike the global genetic deletion of GluA1, inducible GluA1 ablation during late adolescence resulted in normal sociability. Deletion of GluA1 induced redistribution of GluA2 subunits, suggesting AMPA receptor trafficking deficits. Mutant animals showed increased hippocampal NMDA receptor expression and no change in striatal dopamine concentration. Our data provide new insight into the role of deficient AMPA receptors specifically during late adolescence in inducing several cognitive and behavioral alterations with possible relevance for neuropsychiatric disorders.
Assuntos
Transtornos Cognitivos/metabolismo , Corpo Estriado/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Receptores de AMPA/metabolismo , Comportamento Social , Animais , Corpo Estriado/crescimento & desenvolvimento , Dopamina/metabolismo , Hipocampo/crescimento & desenvolvimento , Aprendizagem em Labirinto/fisiologia , Memória de Curto Prazo , Transtornos Mentais , Camundongos , Camundongos Transgênicos , Atividade Motora/fisiologia , Fenótipo , Receptores de AMPA/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Filtro Sensorial/fisiologiaRESUMO
The glutamate hypothesis of schizophrenia postulates NMDA receptor hypofunction as important pathophysiological mechanism. In rodents, NMDA receptor antagonists induce together with psychosis-like effects cortical injury. Stress during adolescence can trigger schizophrenia by unknown mechanisms. Here we show in rats that juvenile chronic isolation significantly increases MK-801-triggered expression of heat shock protein 70, a marker of neuronal injury, in the retrosplenial cortex. These data suggest an additive effect of juvenile stress and NMDA receptor blockade, with possible relevance for schizophrenia.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Maleato de Dizocilpina/toxicidade , Antagonistas de Aminoácidos Excitatórios/toxicidade , Neurônios/efeitos dos fármacos , Neurotoxinas/toxicidade , Isolamento Social , Animais , Córtex Cerebral/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Masculino , Neurônios/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVES: The main aims of this paper are to review and evaluate the neurobiology of the depressive syndrome from a neurodevelopmental perspective. METHODS: An English language literature search was performed using PubMed. RESULTS: Depression is a complex syndrome that involves anatomical and functional changes that have an early origin in brain development. In subjects with genetic risk for depression, early stress factors are able to mediate not only the genetic risk but also gene expression. There is evidence that endocrine and immune interactions have an important impact on monoamine function and that the altered monoamine signalling observed in the depressive syndrome has a neuro-endocrino-immunological origin early in the development. CONCLUSIONS: Neurodevelopment is a key aspect to understand the whole neurobiology of depression.
Assuntos
Encéfalo/crescimento & desenvolvimento , Transtorno Depressivo , Interação Gene-Ambiente , Encéfalo/patologia , Transtorno Depressivo/etiologia , Transtorno Depressivo/genética , Transtorno Depressivo/imunologia , Transtorno Depressivo/metabolismo , HumanosAssuntos
Proteínas Proto-Oncogênicas c-fos/biossíntese , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenóis/farmacologia , Piperidinas/farmacologia , Subunidades Proteicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Recently, there has been renewed interest in the role played by microbiome in both human health and human disease. A correct equilibrium between the human host and their microorganisms is important for an appropriate physiological function. Extensive research has shown that microbes that inhabit the gastrointestinal tract-or gut microbiota-are involved not only in both nutritive and digestive activities but also in immunological processes. Moreover, the gut microbiome influences both central nervous system and energy homeostasis. An altered gut microbiome has been associated with the pathophysiology of different diseases, including neuropsychiatric disorders. Apparently, both environmental-diet, exposition to antibiotics, and infections-and host-genetic factors have a strong influence on gut microbiome, modulating the risk for neuropsychiatric illness. Also, early life disruption of the microbiome-gut-brain (MGB) axis has been associated with an increased risk of developing depression later in life, suggesting a link between gut microbiome, neurodevelopment, and depression. This review aims to contribute to this growing area of research by exploring the role played by the gut microbiome in neurodevelopment and in the etiology of the depressive syndrome, including nutritional, immunological, and energy homeostasis approaches.
RESUMO
Several prospective studies indicated perinatal hypoxia as risk factor for psychiatric disorders like schizophrenia. It is thought that hypoxia prior to or during birth may contribute to alterations leading to the protracted clinical manifestation during young adulthood. However, only a small fraction of children with a history of perinatal hypoxia develop later psychotic symptoms, therefore it is not known if hypoxia alone is sufficient to trigger long-term behavioral changes. Here we exposed C57BL/6 mice from postnatal day 3-7 (P3-P7) to two established paradigms of chronic mild hypoxia (10% ambient O2), intermittent and continuous. Subsequently, mice were analysed during young adult stages using several basic behavioral tests. Previous studies demonstrated severe, but only transient, cortical damage in these paradigms; it is not clear, if these reversible morphological changes are accompanied by long-term behavioral effects. We found that neither intermittent nor continuous perinatal hypoxia induced long-term behavioral alterations. This may be due to the high regenerative capacity of the perinatal brain. Other possibilities include a potential resistance to perinatal hypoxia of the mouse strain used here or a level of hypoxia that was insufficient to trigger significant behavioral changes. Therefore, our data do not exclude a role of perinatal hypoxia as risk factor for psychiatric disorders. They rather suggest that either other, more severe hypoxic conditions like anoxia, or the presence of additional factors (as genetic risk factors) are necessary for generating long-term behavioral abnormalities.
Assuntos
Comportamento Animal , Hipóxia/psicologia , Animais , Comportamento Exploratório , Hipóxia/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora , Esquizofrenia/etiologia , Filtro SensorialRESUMO
NMDA receptor (NMDAR) antagonists like ketamine and MK-801 possess remarkable antidepressant effects with fast onset. However, they over-stimulate the retrosplenial cortex, evoking psychosis-like effects and neuronal injury, revealed by de novo induction of the heat shock protein 70 (Hsp70). Moreover, early in the development MK-801 triggers widespread cortical apoptosis, inducing extensive caspase-3 expression. Altogether these data raise strong concerns on the clinical applicability of NMDAR antagonist therapies. Therefore, the development of novel therapeutics targeting more specifically NMDAR to avoid psychotomimetic effects is necessary. Here we investigated a GluN2B (NR2B) antagonist in behavioral and neurotoxicity paradigms in rats to assess its potential as possible alternative to unspecific NMDA receptor antagonists. We found that treatment with the GluN2B specific antagonist Ro 25-6981 evoked robust antidepressant-like effects. Moreover, Ro 25-6981 did not cause hyperactivity as displayed after treatment with unspecific NMDAR antagonists, a correlate of psychosis-like effects in rodents. Additionally, Ro 25-6981, unlike MK-801, did not induce caspase-3 and HSP70 expression, markers of neurotoxicity in the perinatal and adult brain, respectively. Moreover, unexpectedly, in the adult retrosplenial cortex Ro 25-6981 pretreatment significantly reduced MK-801-triggered neurotoxicity. Our results suggest that GluN2B antagonists may represent valuable alternatives to unspecific NMDAR antagonists with robust antidepressant efficacy and a more favorable side-effect profile.
Assuntos
Antidepressivos/farmacologia , Degeneração Neural/induzido quimicamente , Fenóis/farmacologia , Piperidinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Fatores Etários , Animais , Caspase 3/metabolismo , Maleato de Dizocilpina/antagonistas & inibidores , Maleato de Dizocilpina/farmacologia , Interações Medicamentosas , Feminino , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Alucinógenos/antagonistas & inibidores , Alucinógenos/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , RatosRESUMO
Electroconvulsive therapy (ECT) is an effective therapy for several psychiatric disorders, including severe major depression, mania and certain forms of schizophrenia. It had been proposed that ECT acts by modulating local plasticity via the stimulation of neurogenesis. In fact, among antidepressant therapies, ECT is the most robust enhancer of neurogenesis in the hippocampus of rodents and non-human primates. The existence of ECT-triggered neurogenesis in other brain areas, particularly in those adjacent to the other main locus of neurogenesis, the subventricular zone (SVZ), had so far remained unknown. Here we show that ECT also strongly enhances neurogenesis in frontal brain areas, especially in the rostro-medial striatum, generating specific, small-size calretinin-positive interneurons. We provide here the first evidence that ECT stimulates neurogenesis in areas outside the hippocampus. Our data may open research possibilities that focus on the plastic changes induced by ECT in frontal limbic circuitry.
Assuntos
Eletroconvulsoterapia , Lobo Frontal/fisiopatologia , Neurogênese , Animais , Animais Recém-Nascidos , Bromodesoxiuridina/metabolismo , Contagem de Células , Proteínas do Domínio Duplacortina , Humanos , Interneurônios/metabolismo , Interneurônios/patologia , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Neostriado/metabolismo , Neostriado/patologia , Neostriado/fisiopatologia , Neuropeptídeos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Schizophrenia is most likely a neurodevelopmental disorder with a characteristic delayed onset of symptoms occurring usually during transition from adolescence to adulthood. Recent studies revealed that both genetic and environmental risk factors for the disease disturb not only embryonic, but also postnatal neurogenesis, possible contributing to neurochemical alterations associated with schizophrenia. Several recent patents proposed therapeutic interventions in schizophrenia by increasing postnatal neurogenesis. It remains, however, unclear, how such pro-neurogenic interventions could ameliorate alterations in neurotransmitter systems associated with the disease, such as the dopamine system. Here we review these patents in the context of the existent data about postnatal neurogenesis in the subventricular zone in rodents and primates. We discuss also in light of a recently proposed theoretical model the possible relevance of disturbed neurogenesis for the dopamine system, focusing on the dopamine receptors associated with neurogenesis, the D3 receptors, and a D3-expressing structure derived from the subventricular zone, the Islands of Calleja. Finally, we discuss these findings in the light of molecular imaging studies in early schizophrenia.
Assuntos
Gânglios da Base/metabolismo , Desenvolvimento Infantil , Dopamina/metabolismo , Ínsulas Olfatórias/metabolismo , Neurogênese , Neurônios/metabolismo , Transtornos Psicóticos/metabolismo , Adolescente , Desenvolvimento do Adolescente/efeitos dos fármacos , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Gânglios da Base/efeitos dos fármacos , Criança , Desenvolvimento Infantil/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/uso terapêutico , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Humanos , Ínsulas Olfatórias/efeitos dos fármacos , Terapia de Alvo Molecular , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Patentes como Assunto , Transtornos Psicóticos/tratamento farmacológico , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Receptores de Dopamina D3/metabolismoRESUMO
Glutamatergic agents have been conceptualized as powerful, fast-acting alternatives to monoaminergic-based antidepressants. NMDA receptor antagonists such as ketamine or MK-801 are therapeutically effective, but their clinical use is hampered by psychotomimetic effects, accompanied by neurotoxicity in the retrosplenial and cingulate cortex. Antagonists of metabotropic mGlu5 receptors like MPEP elicit both robust antidepressant and anxiolytic effects; however, the underlying mechanisms are yet unknown. mGlu5 receptors closely interact with NMDA receptors, but whether MPEP induces neurotoxicity similar to NMDA receptor antagonists has not been elucidated. We show here using c-Fos brain mapping that MPEP administration results in a restricted activation of distinct stress-related brain areas, including the bed nucleus of stria terminalis (BNST), central nucleus of the amygdala, and paraventricular nucleus of the hypothalamus (PVNH), in a pattern similar to that induced by classical antidepressants and anxiolytics. Unlike the NMDA antagonist MK-801, MPEP does not injure the adult retrosplenial cortex, in which it fails to induce heat shock protein 70 (Hsp70). Moreover, MPEP does not elicit to the same extent as MK-801 apoptosis in cortical areas at perinatal stages, as revealed by caspase 3 expression. These data identify new cellular targets for the anxiolytic and antidepressant effect of MPEP, indicating also in addition that in contrast to MK-801, it lacks the cortical neurotoxicity associated with psychotomimetic side-effects.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Contagem de Células , Maleato de Dizocilpina/farmacologia , Proteínas de Choque Térmico HSP72/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptor de Glutamato Metabotrópico 5 , Núcleos Septais/efeitos dos fármacos , Núcleos Septais/metabolismoRESUMO
The early postnatal period represents a critical time window for brain development. Transient Cajal-Retzius cells in layer I of the cortex play an important role in cortical lamination by modulating neuronal migration and maturation. Recent data have demonstrated that the 5-HT(3) receptor antagonist and alpha7 nicotinic receptor partial agonist tropisetron, acting via 5-HT(3) receptors expressed on Cajal-Retzius cells, can disturb the formation of cortical columns at perinatal stages. This process is thought to be involved in several neuropsychiatric disorders. Here we investigated the possible long-term behavioral effects of exposure to tropisetron at early postnatal stages in mice. We found that the administration of 1mg/kg, intraperitoneal (i.p.) tropisetron from postnatal days 2-12 (P2-P12) did not induce significant cognitive, schizophrenia-like or emotional alterations in tropisetron-treated animals as compared to controls, when tested in multiple behavioral assays. These results may be of relevance regarding the possible protracted deleterious neuropsychiatric effects of tropisetron during early life.