RESUMO
We previously demonstrated that prenatal exposure to valproic acid (VPA), an environmental model of autism spectrum disorder (ASD), leads to a hyperexcitable phenotype associated with downregulation of inward-rectifying potassium currents in nucleus accumbens (NAc) medium spiny neurons (MSNs) of adolescent rats. Aberrant mTOR pathway function has been associated with autistic-like phenotypes in multiple animal models, including gestational exposure to VPA. The purpose of this work was to probe the involvement of the mTOR pathway in VPA-induced alterations of striatal excitability. Adolescent male Wistar rats prenatally exposed to VPA were treated acutely with the mTOR inhibitor rapamycin and used for behavioral tests, ex vivo brain slice electrophysiology, single-neuron morphometric analysis, synaptic protein quantification and gene expression analysis in the NAc. We report that postnatal rapamycin ameliorates the social deficit and reverts the abnormal excitability, but not the inward-rectifying potassium current defect, of accumbal MSNs. Synaptic transmission and neuronal morphology were largely unaffected by prenatal VPA exposure or postnatal rapamycin treatment. Transcriptome analysis revealed extensive deregulation of genes implied in neurodevelopmental disorders and ionic mechanisms exerted by prenatal VPA, which was partially reverted by postnatal rapamycin. The results of this work support the existence of antagonistic interaction between mTOR and VPA-induced pathways on social behavior, neurophysiological phenotype and gene expression profile, thus prompting further investigation of the mTOR pathway in the quest for specific therapeutic targets in ASD.
Assuntos
Transtorno do Espectro Autista , Efeitos Tardios da Exposição Pré-Natal , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/metabolismo , Comportamento Animal , Modelos Animais de Doenças , Feminino , Masculino , Neurônios/metabolismo , Fenótipo , Potássio , Gravidez , Ratos , Ratos Wistar , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Ácido Valproico/farmacologiaRESUMO
Earlier studies have shown a major involvement of Ventral Tegmental Area (VTA) dopamine (DA) neurons in mediating the rewarding effects of ethanol (EtOH). Much less is known on the role of this system in mediating the transition from moderate to excessive drinking and abuse. Here we sought to explore the hypothesis that early stage drinking in rodents, resembling recreational EtOH use in humans, is sufficient to dysregulate VTA DA transmission thus increasing the propensity to use over time. To this purpose, midbrain slice recordings in mice previously exposed to an escalating (3, 6 and 12%) 18-day voluntary EtOH drinking paradigm was used. By recording from DA and γ-aminobutyric acid (GABA) VTA neurons in midbrain slices, we found that moderate EtOH drinking leads to a significant suppression of the spontaneous activity of VTA DA neurons, while increasing their response to acute EtOH application. We also found that chronic EtOH leads to the enhancement of GABA input frequency onto a subset of DA neurons. Structurally, chronic EtOH induced a significant increase in the number of GABA axonal boutons contacting DA neurons, suggesting deep rewiring of the GABA network. This scenario is consistent with a downmodulation of the reward DA system induced by moderate EtOH drinking, a neurochemical state defined as "hypodopaminergic" and previously associated with advanced stages of drug use in humans. In this context, increased sensitivity of DA neurons towards acute EtOH may represent the neurophysiological correlate of increased unitary rewarding value, possibly driving progression to addiction.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Neurônios Dopaminérgicos/metabolismo , Etanol/administração & dosagem , Neurônios GABAérgicos/metabolismo , Transmissão Sináptica/fisiologia , Área Tegmentar Ventral/metabolismo , Animais , Neurônios Dopaminérgicos/efeitos dos fármacos , Feminino , Neurônios GABAérgicos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Transmissão Sináptica/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
A 9-year-old girl was diagnosed as having a linear sebaceous nevus syndrome (LSNS). The nevus sebaceus was located on the face, and the girl also had nevoid hypertrichosis on the neck, sensorineural deafness, partial anodontia, blocked tear ducts, labiopalatoschisis, and an area of micropolygyria in the left encephalic (cerebral) hemisphere. Electroencephalographic alterations were detected, but they were not accompanied by a history of seizures; furthermore, the child was not mentally retarded. This phenotypic pattern of LSNS is unusual for the rarity of associated abnormalities.
Assuntos
Anormalidades Múltiplas/patologia , Nevo/complicações , Nevo/patologia , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Angiografia Cerebral , Criança , Eletroencefalografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Nevo/diagnóstico , Nevo/fisiopatologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/fisiopatologia , SíndromeRESUMO
We compared 1.5 T magnetic resonance (MR) image findings in 193 patients with congenital pituitary insufficiency. One hundred and thirty nine of the MR studies were obtained in patients who had isolated growth hormone deficiency (GHD). Other fifty-four patients had multiple pituitary hormone deficiency (MPHD). On MR images, normal anterior and posterior lobes of the pituitary gland can be clearly differentiated because the posterior lobe has a characteristic high intensity on T1-weighted images. In fifty-four patients, the high-intensity of the posterior lobe was not seen, but a similar high signal intensity was observed at the proximal stump in fifty-one patients. This high-intensity area is the newly formed ectopic posterior lobe, which also secrets anti-diuretic hormone just as the posterior lobe would. MR imaging can demonstrate the transection of the pituitary stalk and the formation of the ectopic lobe, revealing to be a usefull diagnostic tool in the definition of the type of alteration in growth defects of endocrine origin.