RESUMEN
Schizophrenia is a debilitating psychiatric disorder with a significant number of patients not adequately responding to treatment. Phencyclidine (PCP) is used as a validated model for schizophrenia, shown to reliably induce positive, negative and cognitive-like behaviors in rodents. It was previously shown in our lab that behavioral phenotypes of PCP-treated mice can be alleviated after intracranial transplantation of mesenchymal stem cells (MSC). Here, we assessed the feasibility of intranasal delivery of MSCs-derived-extracellular vesicles (EVs) to alleviate schizophrenia-like behaviors in a PCP model of schizophrenia. As MSCs-derived EVs were already shown to concentrate at the site of lesion in the brain, we determined that in PCP induced injury the EVs migrate to the prefrontal cortex (PFC) of treated mice, a most involved area of the brain in schizophrenia. We show that intranasal delivery of MSC-EVs improve social interaction and disruption in prepulse inhibition (PPI) seen in PCP-treated mice. In addition, immunohistochemical studies demonstrate that the EVs preserve the number of parvalbumin-positive GABAergic interneurons in the PFC of treated mice. Finally, MSCs-EVs reduced glutamate levels in the CSF of PCP-treated mice, which might explain the reduction of toxicity. In conclusion, we show that MSCs-EVs improve the core schizophrenia-like behavior and biochemical markers of schizophrenia and might be used as a novel treatment for this incurable disorder.
Asunto(s)
Vesículas Extracelulares , Células Madre Mesenquimatosas , Esquizofrenia , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Fenciclidina , Corteza Prefrontal , Esquizofrenia/terapiaRESUMEN
In the original Article, Dr. Angela Ruban's name was misspelled as "Aangela Ruban". This has been corrected in the PDF, HTML, and XML versions of this Article.
RESUMEN
The etiology of major neurodevelopmental disorders such as schizophrenia and autism is unclear, with evidence supporting a combination of genetic factors and environmental insults, including viral infection during pregnancy. Here we utilized a mouse model of maternal immune activation (MIA) with the viral mimic PolyI:C infection during early gestation. We investigated the transcriptional changes in the brains of mouse fetuses following MIA during the prenatal period, and evaluated the behavioral and biochemical changes in the adult brain. The results reveal an increase in RNA editing levels and dysregulation in brain development-related gene pathways in the fetal brains of MIA mice. These MIA-induced brain editing changes are not observed in adulthood, although MIA-induced behavioral deficits are observed. Taken together, our findings suggest that MIA induces transient dysregulation of RNA editing at a critical time in brain development.
Asunto(s)
Trastornos del Neurodesarrollo/etiología , Trastornos del Neurodesarrollo/genética , Complicaciones del Embarazo/inmunología , Embarazo/inmunología , Efectos Tardíos de la Exposición Prenatal/genética , Edición de ARN , Animales , Conducta Animal , Encéfalo/crecimiento & desarrollo , Encéfalo/inmunología , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Femenino , Inmunidad Materno-Adquirida , Ratones , Ratones Endogámicos C57BL , Trastornos del Neurodesarrollo/inmunología , Trastornos del Neurodesarrollo/psicología , Poli I-C/efectos adversos , Poli I-C/inmunología , Complicaciones del Embarazo/etiología , Complicaciones del Embarazo/genética , Efectos Tardíos de la Exposición Prenatal/inmunología , Efectos Tardíos de la Exposición Prenatal/psicologíaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.