RESUMO
Maternal immune activation (MIA) during pregnancy in rodents increases the risk of the offspring to develop schizophrenia-related behaviors, suggesting a relationship between the immune system and the brain development. Here we tested the hypothesis that MIA induced by the viral mimetic polyinosinic-polycytidylic acid (poly I:C) in early or late gestation of mice leads to behavioral and neuroanatomical disorders in the adulthood. On gestational days (GDs) 9 or 17 pregnant dams were treated with poly I:C or saline via intravenous route and the offspring behaviors were measured during adulthood. Considering the progressive structural neuroanatomical alterations in the brain of individuals with schizophrenia, we used magnetic resonance imaging (MRI) to perform brain morphometric analysis of the offspring aged one year. MIA on GD9 or GD17 led to increased basal locomotor activity, enhanced motor responses to ketamine, a psychotomimetic drug, and reduced time spent in the center of the arena, suggesting an increased anxiety-like behavior. In addition, MIA on GD17 reduced glucose preference in the offspring. None of the treatments altered the relative volume of the lateral ventricles. However, a decrease in brain volume, especially for posterior structures, was observed for one-year-old animals treated with poly I:C compared with control groups. Thus, activation of the maternal immune system at different GDs lead to neuroanatomical and behavioral alterations possibly related to the positive and negative symptoms of schizophrenia. These results provide insights on neuroimmunonological and neurodevelopmental aspects of certain psychopathologies, such as schizophrenia.
Assuntos
Encéfalo/patologia , Transtornos Mentais/etiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Esquizofrenia/complicações , Esquizofrenia/etiologia , Esquizofrenia/patologia , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Encéfalo/diagnóstico por imagem , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Preferências Alimentares , Indutores de Interferon/toxicidade , Ketamina/toxicidade , Locomoção/fisiologia , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C/toxicidade , Gravidez , Esquizofrenia/diagnóstico por imagem , Sacarose/administração & dosagemRESUMO
Cannabinoids and drugs that increase endocannabinoid levels inhibit neuronal excitability and restrain epileptic seizures through CB1 receptor activation. Nevertheless, the results have not been entirely consistent, since pro-convulsant effects have also been reported. The present study aimed to further investigate the effects of cannabinoid-related compounds on seizures induced by pentylenetetrazole (PTZ) in rats. Video-EEG recordings were used to determine both electrographic and behavioral thresholds to ictal activity. The animals received injections of WIN-55,212-2 (0.3-3 mg/kg, non-selective) or ACEA (1-4 mg/kg, CB1-selective), two synthetic cannabinoids, or URB-597 (0.3-3 mg/kg), an anandamide-hydrolysis inhibitor (FAAH enzyme inhibitor), followed by PTZ. Both WIN-55,212-2 (1 mg/kg) and ACEA (1-4 mg/kg) reduced the threshold for myoclonic seizures and enhanced epileptiform EEG activity, typical pro-convulsive effects. On the contrary, URB-597 (1 mg/kg) had an anti-convulsive effect, as it increased the threshold for the occurrence of minimal seizures and reduced EEG epileptiform activity. None of the drugs tested altered the tonic-clonic maximal seizure threshold. These data suggest that the effects of CB1 signaling upon seizure activity may depend on how this receptor is activated. Contrary to direct agonists, drugs that increase anandamide levels seem to promote an optimal tonus and represent a promising strategy for treating myoclonic seizures.
Assuntos
Benzamidas/uso terapêutico , Canabinoides/uso terapêutico , Carbamatos/uso terapêutico , Endocanabinoides/uso terapêutico , Convulsões/tratamento farmacológico , Animais , Benzoxazinas/uso terapêutico , Convulsivantes/antagonistas & inibidores , Modelos Animais de Doenças , Eletroencefalografia/métodos , Hidrólise , Masculino , Morfolinas/uso terapêutico , Naftalenos/uso terapêutico , Pentilenotetrazol , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/fisiopatologiaRESUMO
The pilocarpine (PILO) animal model of Temporal Lobe Epilepsy (TLE) portrays the most common changes in hippocampal circuitry found in human TLE. The acute cholinergic insult induces status epilepticus (SE), which triggers an overwhelming set of plastic events that result on late spontaneous recurrent limbic seizures. It has been suggested that the cholinergic system plays an important role in the synchronization required for ictogenesis. We took advantage of a knock-down animal model for the vesicular acetylcholine transporter (VAChT KD) to investigate seizure genesis in a model of cholinergic dysfunction. We induced SE in VAChT KD and wild-type (WT) mice by a single intraperitoneal injection of PILO in order to evaluate susceptibility to seizures. Video-EEG recordings evaluated epileptiform activity and ictal behavior onset. The hypothesis tested is that innate cholinergic hypofunction could result in increased susceptibility to PILO. VAChT KD(HOM) mice showed shorter latency for the first epileptiform discharge and for the first seizure episode, when compared to other groups. The duration of these seizure episodes, however, were not statistically different among experimental groups. On the other hand, VAChT KD(HOM) had the shortest latency to isoelectric EEG, when compared to WT and KD(HET). Our results indicate that a reduction of brain VAChT protein to the levels found in VAChT KD(HOM) mice alters the epileptic response to PILO. Thus, fine-tuning modulation of cholinergic tone can affect the susceptibility of epileptic responses to pilocarpine.