RESUMEN
Dysfunctional sensory systems, including altered olfactory function, have recently been reported in patients with autism spectrum disorder (ASD). Disturbances in olfactory processing can potentially result from gamma-aminobutyric acid (GABA)ergic synaptic abnormalities. The specific molecular mechanism by which GABAergic transmission affects the olfactory system in ASD remains unclear. Therefore, the present study aimed to evaluate selected components of the GABAergic system in olfactory brain regions and primary olfactory neurons isolated from Shank3-deficient (-/-) mice, which are known for their autism-like behavioral phenotype. Shank3 deficiency led to a significant reduction in GEPHYRIN/GABAAR colocalization in the piriform cortex and in primary neurons isolated from the olfactory bulb, while no change of cell morphology was observed. Gene expression analysis revealed a significant reduction in the mRNA levels of GABA transporter 1 in the olfactory bulb and Collybistin in the frontal cortex of the Shank3-/- mice compared to WT mice. A similar trend of reduction was observed in the expression of Somatostatin in the frontal cortex of Shank3-/- mice. The analysis of the expression of other GABAergic neurotransmission markers did not yield statistically significant results. Overall, it appears that Shank3 deficiency leads to changes in GABAergic synapses in the brain regions that are important for olfactory information processing, which may represent basis for understanding functional impairments in autism.
Asunto(s)
Trastorno del Espectro Autista , Corteza Olfatoria , Humanos , Ratones , Animales , Trastorno del Espectro Autista/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Sinapsis/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Corteza Olfatoria/metabolismo , Proteínas de Microfilamentos/metabolismoRESUMEN
Oxytocin plays an important role in brain development and is associated with various neurotransmitter systems in the brain. Abnormalities in the production, secretion, and distribution of oxytocin in the brain, at least during some stages of the development, are critical for the pathogenesis of neuropsychiatric diseases, particularly in the autism spectrum disorder. The etiology of autism includes changes in local sensory and dopaminergic areas of the brain, which are also supplied by the hypothalamic sources of oxytocin. It is very important to understand their mutual relationship. In this review, the relationship of oxytocin with several components of the dopaminergic system, gamma-aminobutyric acid (GABA) inhibitory neurotransmission and their alterations in the autism spectrum disorder is discussed. Special attention has been paid to the results describing a reduced expression of inhibitory GABAergic markers in the brain in the context of dopaminergic areas in various models of autism. It is presumed that the altered GABAergic neurotransmission, due to the absence or dysfunction of oxytocin at certain developmental stages, disinhibits the dopaminergic signaling and contributes to the autism symptoms.
Asunto(s)
Trastorno Autístico , Encéfalo , Dopamina , Oxitocina , Ácido gamma-Aminobutírico , Oxitocina/metabolismo , Oxitocina/fisiología , Humanos , Dopamina/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Trastorno Autístico/metabolismo , Encéfalo/metabolismo , Animales , Transmisión Sináptica/fisiología , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/etiologíaRESUMEN
Objective. Modified levels of pro- (caspase3, Bax) and anti-apoptotic (Bcl-2) regulatory proteins have been detected in certain brain areas of schizophrenic patients indicating a possible dysregulation of apoptosis. In the present study, effects of antipsychotics, haloperidol (HAL) and olanzapine (OLA), on the gene expression of caspase3 (casp3), Bax and Bcl-2 were studied in vitro in mouse hippocampal mHippoE-2 cell line and in vivo in the hippocampus of MK-801 animal schizophrenia model with the aim to provide evidence that antipsychotics may affect the activity of apoptosis-related markers. Methods. mHippoE-2 cells were incubated with MK-801 (20 µM), HAL (10 µM), and OLA (10 µM) alone or combined, MK-801+HAL/OLA, for 24, 48, and 72 h. Male Sprague Dawley rats were injected with saline or MK-801 (0.5 mg/kg) for 6 days and since the 7th day, they were treated with vehicle (VEH), HAL (1 mg/kg) or OLA (2 mg/kg) for the next 7 days. The casp3, Bax and Bcl-2 gene expression in mHippoE-2 cells and rat hippocampus was measured by RT-PCR. Results. In mHippoE-2 cells, casp3 gene expression was increased by MK-801 and OLA treatments alone for 48 h, HAL treatment alone for 24 and 72 h, and co-treatment with MK-801+OLA for 24 and 72 h compared to controls. HAL and OLA suppressed the stimulatory effect of MK-801 on casp3 mRNA levels in cells after 48 h of incubation. Bax mRNA levels in mHippoE-2 cells were decreased after HAL treatment for 24 and 48 h, and also after co-treatment with MK-801+HAL for 72 h. In vivo, MK-801 decreased mRNA levels of both pro-apoptotic markers, casp3 and Bax, in hippocampus of VEH-treated rats and Bax mRNA levels in hippocampus of HAL-treated animals. OLA reversed the inhibitory effect of MK-801 on casp3 expression in the VEH-treated animals. Neither MK-801 nor antipsychotics induced changes in the gene expression of anti-apoptotic marker Bcl-2 in mHippoE-2 cells as well as hippocampus of rats. Conclusions. The results of the present study demonstrate that antipsychotics, HAL and OLA, may affect mRNA levels of pro-apoptotic markers in hippocampal cells in vitro, but not in vivo. The obtained data do not clearly support the assumed potentiating role of MK-801 in inducing apoptosis in specific brain areas and a possible protective role of antipsychotics against induction of apoptosis. The obtained data may contribute to a deeper insight into the neurodevelopmental changes connected with schizophrenia.
Asunto(s)
Antipsicóticos , Ratas , Masculino , Ratones , Animales , Antipsicóticos/farmacología , Haloperidol/farmacología , Olanzapina/farmacología , Caspasa 3/farmacología , Maleato de Dizocilpina/farmacología , Proteína X Asociada a bcl-2/genética , Benzodiazepinas/farmacología , Ratas Sprague-Dawley , Apoptosis , HipocampoRESUMEN
The neurobiology of autism is complex, but emerging research points to potential abnormalities and alterations in neurogenesis. The aim of the present review is to describe the advances in the understanding of the role of selected neurotrophins, neuropeptides, and other compounds secreted by neuronal cells in the processes of postnatal neurogenesis in conjunction with autism. We characterize the fundamental mechanisms of neuronal cell proliferation, generation of major neuronal cell types with special emphasis on neurogenic niches - the subventricular zone and hippocampal areas. We also discuss changes in intracellular calcium levels and calcium-dependent transcription factors in the context of the regulation of neurogenesis and cell fate determination. To sum up, this review provides specific insight into the known association between alterations in the function of the entire spectrum of molecules involved in neurogenesis and the etiology of autism pathogenesis.
RESUMEN
Aberrant neurogenesis in the subventricular zone (SVZ) and hippocampus (HIP) contributes to schizophrenia pathogenesis. Haloperidol (HAL) and olanzapine (OLA), commonly prescribed antipsychotics for schizophrenia treatment, affect neurogenesis too. The effect of HAL and OLA on an mHippoE-2 cell line was studied in vitro where we measured the cell number and projection length. In vivo, we studied the gene expression of DCX, Sox2, BDNF, and NeuN in the SVZ and HIP in an MK-801-induced animal schizophrenia model. Cells were incubated with HAL, OLA, and MK-801 for 24, 48, and 72 h. Animals were injected for 6 days with saline or MK801 (0.5 mg/kg), and from the 7th day with either vehicle HAL (1 mg/kg) or OLA (2 mg/kg), for the next 7 days. In vitro, HAL and OLA dose/time-dependently suppressed cells' proliferation and shortened their projection length. HAL/OLA co-treatment with MK-801 for 24 h reversed HAL's/OLA's inhibitory effect. In vivo, HAL and OLA suppressed DCX and NeuN genes' expression in the HIP and SVZ. MK-801 decreased DCX and NeuN genes' expression in the HIP and OLA prevented this effect. The data suggest that subchronic HAL/OLA treatment can inhibit DCX and NeuN expression. In an MK-801 schizophrenia model, OLA reversed the MK-801 inhibitory effect on DCX and NeuN and HAL reversed the effect on DCX expression; however, only in the HIP.
Asunto(s)
Antipsicóticos , Esquizofrenia , Animales , Antipsicóticos/uso terapéutico , Benzodiazepinas , Proliferación Celular , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Haloperidol/farmacología , Haloperidol/uso terapéutico , Hipocampo , Olanzapina/farmacología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genéticaRESUMEN
Alterations in the balance between excitation and inhibition, especially in the brain's critical developmental periods, are considered an integral part of the pathophysiology of autism. However, the precise mechanisms have not yet been established. SH3 and multiple Ankyrin repeat domains 3 (Shank3) deficient mice represent a well-established transgenic model of a neurodevelopmental disorder with autistic symptomatology. In this study, we characterize the consequences of Shank3 deficiency according to (1) expression of specific markers of different neuronal populations in pups and adult mice and (2) social behaviour and anxiety in adult mice. Our research found enhanced expression of serotonin transporter and choline acetyltransferase in the hippocampus and hypothalamus in Shank3-deficient pups. We demonstrated marked brain region differences in expression of excitatory glutamatergic markers in pups and adult Shank3 deficient mice. We also observed reduced expression of inhibitory GABAergic markers and GABA receptor subunits in several brain areas in both pups and adult Shank3 deficient mice. Further analysis of dopaminergic brain areas (nucleus accumbens, ventral tegmental area) revealed lower expression levels of GABAergic markers in adult Shank3 deficient mice. Adult Shank3- deficient mice exhibited excessive repetitive behaviour, a higher level of anxiety, and lower locomotor activity. Our data support the theory of an imbalance between excitatory and inhibitory neurotransmission in conditions of abnormal SHANK3 protein. We therefore suggest that autism-like conditions are accompanied by reduced expression of GABAergic markers in the brain during early development as well as in the adult age, which could be associated with long-lasting behavioural abnormalities.
Asunto(s)
Modelos Animales de Enfermedad , Proteínas de Microfilamentos/fisiología , Proteínas del Tejido Nervioso/fisiología , Neuronas/patología , Conducta Social , Transmisión Sináptica , Animales , Animales Recién Nacidos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/metabolismoRESUMEN
Objectives. The balance between DNA methylation and demethylation is crucial for the brain development. Therefore, alterations in the expression of enzymes controlling DNA methylation patterns may contribute to the etiology of neurodevelopmental disorders, including autism. SH3 and multiple ankyrin repeat domains 3 (Shank3)-deficient mice are commonly used as a well-characterized transgenic model to investigate the molecular mechanisms of autistic symptoms. DNA methyltransferases (DNMTs), which modulate several cellular processes in neurodevelopment, are implicated in the pathophysiology of autism. In this study, we aimed to describe the gene expression changes of major Dnmts in the brain of Shank3-deficient mice during early development. Methods and Results. The Dnmts gene expression was analyzed by qPCR in 5-day-old homo-zygous Shank3-deficient mice. We found significantly lower Dnmt1 and Dnmt3b gene expression levels in the frontal cortex. However, no such changes were observed in the hippocampus. However, significant increase was observed in the expression of Dnmt3a and Dnmt3b genes in the hypothalamus of Shank3-deficient mice. Conclusions. The present data indicate that abnormalities in the Shank3 gene are accompanied by an altered expression of DNA methylation enzymes in the early brain development stages, therefore, specific epigenetic control mechanisms in autism-relevant models should be more extensively investigated.
Asunto(s)
Trastorno Autístico , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A/genética , Proteínas de Microfilamentos , Proteínas del Tejido Nervioso , Animales , Trastorno Autístico/genética , Modelos Animales de Enfermedad , Epigénesis Genética , Expresión Génica , Ratones , Proteínas de Microfilamentos/genética , Proteínas del Tejido Nervioso/genética , ADN Metiltransferasa 3BRESUMEN
Efforts to overcome multidrug resistance in cancer have led to the development of several novel strategies including photodynamic therapy (PDT). PDT is based on the use of photosensitizers (PSs) photoactivation, which causes the formation of reactive oxygen species that can induce cell death. In the last decade, the development of new PSs has been significantly accelerated. Recently, acridine-3,6-dialkyldithiourea hydrochlorides (AcrDTUs) have been investigated as a new group of PSs and we have shown that PDT/AcrDTUs caused cell death of mouse leukemic cells L1210. In this study, we investigated the efficacy of PDT/AcrDTUs for the treatment of L1210/VCR cells as a model of chemoresistant cells (overexpressing P-glycoprotein, P-gp). The photoactivation (365 nm, 1.05 J/cm2) increased the cytotoxicity of AcrDTUs 10-15 times. Inhibition of P-gp (verapamil) has been shown to have no significant effect on the accumulation of propyl-AcrDTU (the most potent derivative) in L1210/VCR cells. The intracellular distribution of this acridine derivative has been studied. Prior to irradiation of the resistant cells, propyl-AcrDTU was sequestered mainly in the cytosol, partly in the mitochondria, and, unlike in the sensitive cells, the AcrDTU was not found in the lysosomes. PDT with 1 µM propyl-AcrDTU induced cell shrinkage and "ladder DNA" formation, and although a drastic decrease of the intracellular ATP level was observed at the same time, there was no increase in extracellular LDH activity. AIF in the nucleus can induce DNA fragmentation and we have actually observed a mitochondrio-nuclear translocation of AIF. We concluded that AcrDTUs are photocytotoxic against L1210/VCR cells and that mitochondria play an important role in cell death induced by PDT.
Asunto(s)
Fotoquimioterapia , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Acridinas/farmacología , Animales , Resistencia a Múltiples Medicamentos , Ratones , Fármacos Fotosensibilizantes/farmacologíaRESUMEN
Sex-specific differences in brain plasticity appear to be organised by testosterone, which is particularly important during the early stages of development. The main purpose of the present study was to examine the sex differences in mRNA and protein levels of selected cell-adhesion molecules and scaffolding proteins on postnatal days 5 (P5) and 9 (P9) in the rat hippocampus, as well as evaluate the effects of testosterone treatment (100 nM, 48 hr) on synaptic proteins in SH-SY5Y (neuron-like) and U-87MG (astrocyte-like) cells. The gene expression levels of Neuroligin 3 and 'SH3 and multiple ankyrin repeat domains protein' 1 and 3 (SHANK1 and SHANK3) were significantly lower in males compared to females at P5. At P9, a similar significant trend towards a decrease in mRNA expression and protein levels of SHANK3 was found in males. Testosterone treatment induced a significant decrease of Neuroligin 1-3 mRNA expression in both SH-SY5Y and U-87MG cells. SHANK1 and SHANK3 mRNA levels significantly decreased in U-87MG cells response to testosterone presence. The presented results demonstrate that the association of selected postsynaptic cell-adhesion molecules and scaffolding proteins is sex-related. Testosterone appears to be particularly involved in the developmental mechanisms related to neuroplasticity.
Asunto(s)
Hipocampo , Testosterona , Animales , Femenino , Expresión Génica , Masculino , Neuronas , ARN Mensajero/genética , Ratas , Testosterona/farmacologíaRESUMEN
Pathological changes in synapse formation, plasticity, and development are caused by altered trafficking and assembly of postsynaptic scaffolding proteins at sites of glutamatergic and gamma-aminobutyric acid (GABA)ergic synapses, suggesting their involvement in the etiology of neurodevelopmental disorders, including autism. Several autism-related mouse models have been developed in recent years for studying molecular, cellular, and behavioural defects in order to understand the etiology of autism and test the potential treatment strategies. In this review, we explain the role of alterations in selected postsynaptic scaffolding proteins in relevant transgene autism-like mouse models. We also provide a summary of selected animal models by paying special attention to interactions between guanylate kinases or membrane-associated guanylate kinases (MAGUKs), as well as other synapse protein components which form functional synaptic networks. The study of early developmental stages of autism-relevant animal models can help us understand the origin and development of diverse autistic symptomatology.
Asunto(s)
Trastorno del Espectro Autista/metabolismo , Ácido Glutámico/metabolismo , Guanilato-Quinasas/metabolismo , Proteínas de Andamiaje Homer/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Sinapsis/metabolismo , Animales , Modelos Animales de Enfermedad , RatonesRESUMEN
Current understanding of the neuroanatomical abnormalities in autism includes gross anatomical changes in several brain areas and microstructural alterations in neuronal cells as well. There are many controversies in the interpretation of the imaging data, evaluation of volume and size of particular brain areas, and their functional translation into a broad autism phenotype. Critical questions of neuronal pathology in autism include the concept of the reversible plasticity of morphological changes, volume alterations of brain areas, and both short- and long-term consequences of adverse events present during the brain development. At the cellular level, remodeling of the actin cytoskeleton is considered as one of the critical factors associated with the autism spectrum disorders. Alterations in the composition of the neuronal cytoskeleton, in particular abnormalities in the polymerization of actin filaments and their associated proteins underlie the functional consequences in behavior resulting in symptoms and clinical correlates of autism spectrum disorder. In the present review, a special attention is devoted to the role of oxytocin in experimental models of neurodevelopmental disorders manifesting alterations in neuronal morphology.
Asunto(s)
Trastorno del Espectro Autista/patología , Trastorno Autístico/patología , Neuronas/patología , Oxitocina/fisiología , Animales , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/metabolismo , Trastorno Autístico/diagnóstico , Trastorno Autístico/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Forma de la Célula , Tamaño de la Célula , Humanos , Imagen por Resonancia Magnética , Neuronas/metabolismo , Oxitocina/metabolismoRESUMEN
Accumulating evidence suggests that Rho GTPases, together with scaffolding SHANK proteins, and associated signaling pathways play a role in the development of autism symptoms in various conditions. Research data have brought information on multiple intracellular signaling pathways, including Rho-associated protein kinases and serine/threonine-protein kinases involved in cytoskeleton rearranging. Alterations in downstream effectors of GTPase signaling pathways are associated with neurodevelopmental disorders. Bioinformatics and experimental data show that complex genetic and molecular defects (GTPases, actin-binding proteins, kinases, neuropeptides) can result in neuronal remodeling, leading to the functional connectivity deficits that manifest as the heterogeneous autism spectrum phenotype. Finally, the known hormone and neuropeptide oxytocin appears to be a factor for consideration in therapeutic intervention.
Asunto(s)
Proteínas del Tejido Nervioso/metabolismo , Trastornos del Neurodesarrollo/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Animales , Citoesqueleto/metabolismo , Citoesqueleto/patología , Humanos , Trastornos del Neurodesarrollo/patología , Transducción de Señal/fisiología , Quinasas Asociadas a rho/metabolismoRESUMEN
Exogenous and endogenously produced sulfide derivatives, such as H2S/HS-/S2-, polysulfides and products of the H2S/S-nitrosoglutathione interaction (S/GSNO), affect numerous biological processes in which superoxide anion (O2-) and hydroxyl (OH) radicals play an important role. Their cytoprotective-antioxidant and contrasting pro-oxidant-toxic effects have been reported. Therefore, the aim of our work was to contribute to resolving this apparent inconsistency by studying sulfide derivatives/free radical interactions and their consequent biological effects compared to the antioxidants glutathione (GSH) and Trolox. Using the electron paramagnetic resonance (EPR) spin trapping technique and O2-, we found that a polysulfide (Na2S4) and S/GSNO were potent scavengers of O2- and cPTIO radicals compared to H2S (Na2S), GSH and Trolox, and S/GSNO scavenged the DEPMPO-OH radical. As detected by the EPR spectra of DEPMPO-OH, the formation of OH in physiological solution by S/GSNO was suggested. All the studied sulfide derivatives, but not Trolox or GSH, had a bell-shaped potency to decompose H2O2 and produced OH in the following order: S/GSNO > Na2S4 ≥ Na2S > GSH = Trolox = 0, but they scavenged OH at higher concentrations. In studies of the biological consequences of these sulfide derivatives/H2O2 properties, we found the following: (i) S/GSNO alone and all sulfide derivatives in the presence of H2O2 cleaved plasmid DNA; (ii) S/GSNO interfered with viral replication and consequently decreased the infectivity of viruses; (iii) the sulfide derivatives induced apoptosis in A2780 cells but inhibited apoptosis induced by H2O2; and (iv) Na2S4 modulated intracellular calcium in A87MG cells, which depended on the order of Na2S4/H2O2 application. We suggest that the apparent inconsistency of the cytoprotective-antioxidant and contrasting pro-oxidant-toxic biological effects of sulfide derivatives results from their time- and concentration-dependent radical production/scavenging properties and their interactions with O2-, OH and H2O2. The results imply a direct involvement of sulfide derivatives in O2- and H2O2/OH free radical pathways modulating antioxidant/toxic biological processes.
Asunto(s)
Antioxidantes/farmacología , Cromanos/farmacología , Peróxido de Hidrógeno/química , Sulfuro de Hidrógeno/farmacología , Radical Hidroxilo/metabolismo , S-Nitrosoglutatión/farmacología , Sulfuros/farmacología , Superóxidos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Radical Hidroxilo/químicaRESUMEN
Aberrant regulation of oxytocin signaling is associated with the etiology of neurodevelopmental disorders. Synaptic dysfunctions in neurodevelopmental disorders are becoming increasingly known, and their pathogenic mechanisms could be a target of potential therapeutic intervention. Therefore, it is important to pay attention to the role of oxytocin and its receptor in synapse structure, function, and neuron connectivity. An early alteration in oxytocin signaling may disturb neuronal maturation and may have short-term and long-term pathological consequences. At the molecular level, neurodevelopmental disorders include alterations in cytoskeletal rearrangement and neuritogenesis resulting in a diversity of synaptopathies. The presence of oxytocin receptors in the presynaptic and postsynaptic membranes and the direct effects of oxytocin on neuronal excitability by regulating the activity of ion channels in the cell membrane implicate that alterations in oxytocin signaling could be involved in synaptopathies. The ability of oxytocin to modulate neurogenesis, synaptic plasticity, and certain parameters of cytoskeletal arrangement is discussed in the present review.
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Oxitocina/metabolismo , Receptores de Oxitocina/metabolismo , Transducción de Señal/fisiología , Sinapsis/metabolismo , Animales , Humanos , Red Nerviosa/fisiología , Plasticidad Neuronal/fisiología , Oxitocina/genética , Receptores de Oxitocina/genética , Sinapsis/genéticaRESUMEN
The hypothalamus is a source of neural progenitor cells which give rise to different populations of specialized and differentiated cells during brain development. Newly formed neurons in the hypothalamus can synthesize and release various neuropeptides. Although term neuropeptide recently undergoes redefinition, small-size hypothalamic neuropeptides remain major signaling molecules mediating short- and long-term effects on brain development. They represent important factors in neurite growth and formation of neural circuits. There is evidence suggesting that the newly generated hypothalamic neurons may be involved in regulation of metabolism, energy balance, body weight, and social behavior as well. Here we review recent data on the role of hypothalamic neuropeptides in adult neurogenesis and neuritogenesis with special emphasis on the development of food intake and social behavior related brain circuits.
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Hipotálamo/citología , Hipotálamo/fisiología , Neurogénesis/fisiología , Neuropéptidos/fisiología , Animales , Ingestión de Alimentos/fisiología , Metabolismo Energético/fisiología , Humanos , Células-Madre Neurales/fisiología , Neuronas/fisiologíaRESUMEN
Brain oxytocin regulates a variety of social and affiliative behaviors and affects also learning and memory. However, mechanisms of its action at the level of neuronal circuits are not fully understood. The present study tests the hypothesis that molecular factors required for memory formation and synaptic plasticity, including brain-derived neurotrophic factor, neural growth factor, nestin, microtubule-associated protein 2 (MAP2), and synapsin I, are enhanced by central administration of oxytocin. We also investigated whether oxytocin enhances object recognition and acts as anxiolytic agent. Therefore, male Wistar rats were infused continuously with oxytocin (20 ng/µl) via an osmotic minipump into the lateral cerebral ventricle for 7 days; controls were infused with vehicle. The object recognition test, open field test, and elevated plus maze test were performed on the sixth, seventh, and eighth days from starting the infusion. No significant effects of oxytocin on anxious-like behavior were observed. The object recognition test showed that oxytocin-treated rats significantly preferred unknown objects. Oxytocin treatment significantly increased gene expression and protein levels of neurotrophins, MAP2, and synapsin I in the hippocampus. No changes were observed in nestin expression. Our results provide the first direct evidence implicating oxytocin as a regulator of brain plasticity at the level of changes of neuronal growth factors, cytoskeletal proteins, and behavior. The data support assumption that oxytocin is important for short-term hippocampus-dependent memory.
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Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Asociadas a Microtúbulos/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Oxitocina/administración & dosificación , Reconocimiento en Psicología/efectos de los fármacos , Sinapsinas/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Sistemas de Liberación de Medicamentos , Conducta Exploratoria/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Proteínas Asociadas a Microtúbulos/genética , Factores de Crecimiento Nervioso/genética , Ratas , Ratas Wistar , Sinapsinas/genéticaRESUMEN
Oxytocin affects social recognition, interactions, and behavior in adults. Despite growing data on the role of oxytocin in the sensory systems, its effects on early olfactory system development remain poorly understood. The present study aimed to investigate the developmental impact of oxytocin on selected parameters of the GABAergic system in olfactory brain regions. We found a significant increase in the expression of GABAergic markers and scaffolding proteins in the olfactory bulb during the early stages of development in both male and female rats, regardless of oxytocin treatment administered on postnatal days 2 and 3 (P2 and P3, 5 µg/pup). Oxytocin administration markedly reduced the expression of the scaffolding protein Gephyrin in male rats and it led to a significant increase in the number of GABAergic synaptic puncta in the piriform cortex of male rats at P5, P7, and P9. Our data suggest that the developmental action of oxytocin in relation to the GABAergic system may represent a mechanism by which the plasticity and maturation of olfactory brain regions are regulated.
Asunto(s)
Neuronas GABAérgicas , Proteínas de la Membrana , Bulbo Olfatorio , Oxitocina , Animales , Oxitocina/farmacología , Oxitocina/metabolismo , Femenino , Masculino , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/metabolismo , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/metabolismo , Bulbo Olfatorio/crecimiento & desarrollo , Proteínas de la Membrana/metabolismo , Ratas Wistar , Proteínas Portadoras/metabolismo , Ratas , Animales Recién Nacidos , Corteza Piriforme/efectos de los fármacos , Corteza Piriforme/metabolismo , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismoRESUMEN
Neuropeptide oxytocin appears to be involved in the formation of hippocampal circuitry, underlying social memory and behaviour. Recent studies point to the role of oxytocin in regulating the levels of nerve growth factors that could influence neurogenesis and neuritogenesis during the early stages of brain development. Therefore, the aim of the present study was to evaluate the early developmental effect of oxytocin administration (P2 and P3 days, two doses, 5 µg/pup, s.c.) on the expression of 1) brain-derived neurotrophic factor (BDNF) isoforms and 2) GABAergic and glutamatergic markers in the male rat hippocampus. Furthermore, we evaluated the branching of dendrites of primary hippocampal GABAergic and glutamatergic neurons in response to incubation with oxytocin (1 µM). We found that after oxytocin administration, levels of proBDNF increased on P5 and mBDNF on P7 in the CA1 hippocampal region. We also observed a reduction in the expression of glutamatergic marker (VGluT2) on P7 compared to P5 in control and oxytocin treated rats. During the early developmental stages (P5, P7, P9) the expression of GABAergic markers (Gad65 and Gad67) decreased regardless of oxytocin treatment. Incubation in a presence of oxytocin reduced branching of glutamatergic hippocampal neurons and the opposite stimulatory effect of oxytocin was observed in GABAergic neurons. These findings suggest that oxytocin affects neurotrophin isoforms in the male rat hippocampus in the early stages of development, which could explain changes in glutamatergic neurons and their morphology.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Oxitocina , Ratas , Animales , Masculino , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Oxitocina/farmacología , Hipocampo , Neuronas GABAérgicas/metabolismo , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/farmacologíaRESUMEN
Oxytocin, released in response to different physiological stimuli, could play a key role in reducing stress reaction. It was suggested that it has protective effect against inflammation and consequences of oxidative stress. Mechanisms how oxytocin effects mediated in the brain tissue are unclear. In this study, oxytocin effect on cell growth and neuronal viability was examined. Human neuroblastoma (SH-SY5Y and SK-N-SH) and glioblastoma (U87MG) cells were exposed to different concentrations of oxytocin for 12-96 h. Potential protective effect of oxytocin treatment was investigated after exposing cells to oxidative stress using hydrogen peroxide (50 mM, 2 h) or 6-hydroxydopamine (25 µM, 24 h). Cell proliferation was measured by cell counting and cell viability was examined by MTT assay. Protein expression of selected neurotrophic factors was measured as an additional parameter. Oxytocin (1 µM) significantly increased cell number in all three cell types. Viability of SH-SY5Y cells was increased in the presence of oxytocin without significant effect of dose (0.01-1 µM). Cell death induced by hydrogen peroxide was not prevented by incubation with oxytocin. Oxytocin pretreatment blunted neurotoxin 6-OHDA reduction of cell viability in SH-SY5Y cells. Oxytocin (1 µM, 12 h) elevated amount of total proteins without increasing levels of brain-derived neurotrophic factor and neurotrophic growth factor. In conclusion, oxytocin increases growth and viability of neuroblastoma and glioblastoma cells without activation of neurotrophic factors. Oxytocin does not have protective effect in oxidative stress; however, it might be important for neuroprotection to dopaminergic neurons. Its proliferative effect might be important in native cell life, euplastic processes, and tumor progression.
Asunto(s)
Neuroblastoma/patología , Oxitocina/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/farmacología , Neuronas/efectos de los fármacos , Neuronas/patología , Estrés Oxidativo/efectos de los fármacos , Oxidopamina/farmacologíaRESUMEN
Epigenetic mechanisms greatly affect the developing brain, as well as the maturation of synapses with pervasive, long-lasting consequences on behavior in adults. Substantial evidence exists that implicates dysregulation of epigenetic mechanisms in the etiology of neurodevelopmental disorders. Therefore, this review explains the role of enzymes involved in DNA methylation and demethylation in neurodevelopment by emphasizing changes of synaptic genes and proteins. Epigenetic causes of sex-dependent differences in the brain are analyzed in conjunction with the pathophysiology of autism spectrum disorders. Special attention is devoted to the epigenetic regulation of the melanoma-associated antigen-like gene 2 (MAGEL2) found in Prader-Willi syndrome, which is known to be accompanied by autistic symptoms.