RESUMO
Genome-wide association studies (GWAS) for schizophrenia have identified over 100 loci encoding >500 genes. It is unclear whether any of these genes, other than dopamine receptor D2, are immediately relevant to antipsychotic effects or represent novel antipsychotic targets. We applied an in vivo molecular approach to this question by performing RNA sequencing of brain tissue from mice chronically treated with the antipsychotic haloperidol or vehicle. We observed significant enrichments of haloperidol-regulated genes in schizophrenia GWAS loci and in schizophrenia-associated biological pathways. Our findings provide empirical support for overlap between genetic variation underlying the pathophysiology of schizophrenia and the molecular effects of a prototypical antipsychotic.
Assuntos
Corpo Estriado/efeitos dos fármacos , Haloperidol/metabolismo , Esquizofrenia/genética , Animais , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genômica/métodos , Haloperidol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Risco , Psicologia do Esquizofrênico , Análise de Sequência de RNARESUMO
Profound impairment in social interaction is a core symptom of autism, a severe neurodevelopmental disorder. Deficits can include a lack of interest in social contact and low levels of approach and proximity to other children. In this study, a three-chambered choice task was used to evaluate sociability and social novelty preference in five lines of mice with mutations in genes implicated in autism spectrum disorders. Fmr1(tm1Cgr/Y)(Fmr1(-/y)) mice represent a model for fragile X, a mental retardation syndrome that is partially comorbid with autism. We tested Fmr1(-/y)mice on two genetic backgrounds, C57BL/6J and FVB/N-129/OlaHsd (FVB/129). Targeted disruption of Fmr1 resulted in low sociability on one measure, but only when the mutation was expressed on FVB/129. Autism has been associated with altered serotonin levels and polymorphisms in SLC6A4 (SERT), the serotonin transporter gene. Male mice with targeted disruption of Slc6a4 displayed significantly less sociability than wild-type controls. Mice with conditional overexpression of Igf-1 (insulin-like growth factor-1) offered a model for brain overgrowth associated with autism. Igf-1 transgenic mice engaged in levels of social approach similar to wild-type controls. Targeted disruption in other genes of interest, En2 (engrailed-2) and Dhcr7, was carried on genetic backgrounds that showed low levels of exploration in the choice task, precluding meaningful interpretations of social behavior scores. Overall, results show that loss of Fmr1 or Slc6a4 gene function can lead to deficits in sociability. Findings from the fragile X model suggest that the FVB/129 background confers enhanced susceptibility to consequences of Fmr1 mutation on social approach.
Assuntos
Transtorno Autístico/genética , Transtorno Autístico/psicologia , Engenharia Genética , Camundongos Knockout/genética , Camundongos Knockout/psicologia , Comportamento Social , Animais , Ansiedade/psicologia , Comportamento Animal/fisiologia , Comportamento Exploratório/fisiologia , Feminino , Privação de Alimentos/fisiologia , Proteína do X Frágil da Deficiência Intelectual/genética , Proteínas de Homeodomínio/genética , Fator de Crescimento Insulin-Like I/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Proteínas do Tecido Nervoso/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Equilíbrio Postural/fisiologia , Gravidez , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Caracteres Sexuais , Olfato/genética , Olfato/fisiologiaRESUMO
The aim of this study is to identify a possible function of Active Sleep (AS), also known as Rapid Eye Movement Sleep (REM) in humans, as a protective state during early Central Nervous System (CNS) development. Previous research suggest pharmacological agents that inhibit high levels of neuronal activity in the CNS (e.g., benzodiazepines, ethanol, and anesthetics) precipitate massive CNS programmed cell death (PCD), in developing mammals. AS is characterized by high levels of CNS activity at levels comparable to waking. AS occupies up to 75% of the circadian cycle in developing mammals (rodents from postnatal days 1-14 days (p1-p14), and humans from prenatal month seven to postnatal year one). Many studies have implicated AS as having an active role in the normal development of the visual system and have documented myriad behavioral anomalies as a result of AS deprivation. Reduced adult brain mass has also been observed after AS deprivation in developing rats during this period, however, no study to date has documented this process as it occurs (i.e., the cellular mechanisms that result in behavioral anomalies or reduced adult brain mass). The purpose of this study is to begin documentation of this process by utilizing histological techniques that identify the PCD process, if it occurs, after acute and prolonged AS deprivation in rats from ages p7 to p14 (a time of active synaptogenesis). Our methodology includes utilization of the alpha2-adrenergic receptor agonist clonidine, to deprive rat pups of AS at ages varying from p7 to p14. Pilot data from our laboratory has shown that an acute exposure to clonidine significantly reduces time spent in AS. The animals that were AS deprived also showed a statistically significant decrease in brain mass and have stained positively for PCD. If our hypotheses are correct, this research will have major implications with regard to determining the function(s) of REM sleep.
