RESUMEN
BACKGROUND: Autism involves early brain overgrowth and dysfunction, which is most strongly evident in the prefrontal cortex. As assessed on pathological analysis, an excess of neurons in the prefrontal cortex among children with autism signals a disturbance in prenatal development and may be concomitant with abnormal cell type and laminar development. METHODS: To systematically examine neocortical architecture during the early years after the onset of autism, we used RNA in situ hybridization with a panel of layer- and cell-type-specific molecular markers to phenotype cortical microstructure. We assayed markers for neurons and glia, along with genes that have been implicated in the risk of autism, in prefrontal, temporal, and occipital neocortical tissue from postmortem samples obtained from children with autism and unaffected children between the ages of 2 and 15 years. RESULTS: We observed focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in prefrontal and temporal cortical tissue from 10 of 11 children with autism and from 1 of 11 unaffected children. We observed heterogeneity between cases with respect to cell types that were most abnormal in the patches and the layers that were most affected by the pathological features. No cortical layer was uniformly spared, with the clearest signs of abnormal expression in layers 4 and 5. Three-dimensional reconstruction of layer markers confirmed the focal geometry and size of patches. CONCLUSIONS: In this small, explorative study, we found focal disruption of cortical laminar architecture in the cortexes of a majority of young children with autism. Our data support a probable dysregulation of layer formation and layer-specific neuronal differentiation at prenatal developmental stages. (Funded by the Simons Foundation and others.).
Asunto(s)
Trastorno Autístico/patología , Neocórtex/ultraestructura , Adolescente , Trastorno Autístico/genética , Biomarcadores/análisis , Biomarcadores/metabolismo , Calbindina 1/genética , Recuento de Células , Niño , Preescolar , Crioultramicrotomía , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/genética , Expresión Génica , Humanos , Imagenología Tridimensional , Hibridación in Situ , Neocórtex/crecimiento & desarrollo , Proteínas del Tejido Nervioso/genética , Proteínas de Neurofilamentos/genética , Neurogénesis , Neuronas/patología , Miembro 2 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , ARN/genéticaRESUMEN
Data sharing in autism neuroimaging presents scientific, technical, and social obstacles. We outline the desiderata for a data-sharing scheme that combines imaging with other measures of phenotype and with genetics, defines requirements for comparability of derived data and recommendations for raw data, outlines a core protocol including multispectral structural and diffusion-tensor imaging and optional extensions, provides for the collection of prospective, confound-free normative data, and extends sharing and collaborative development not only to data but to the analytical tools and methods applied to these data. A theme in these requirements is the need to preserve creative approaches and risk-taking within individual laboratories at the same time as common standards are provided for these laboratories to build on.
Asunto(s)
Trastorno Autístico/diagnóstico , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Conducta Cooperativa , Trastorno Autístico/epidemiología , Niño , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/epidemiología , Femenino , Humanos , Relaciones Interprofesionales , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Fenotipo , Tomografía de Emisión de Positrones , Percepción SocialRESUMEN
The generation of new neurons from neural stem cells is restricted to two regions of the adult mammalian central nervous system: the subventricular zone of the lateral ventricle, and the subgranular zone of the hippocampal dentate gyrus. In both regions, signals provided by the microenvironment regulate the maintenance, proliferation and neuronal fate commitment of the local stem cell population. The identity of these signals is largely unknown. Here we show that adult hippocampal stem/progenitor cells (AHPs) express receptors and signalling components for Wnt proteins, which are key regulators of neural stem cell behaviour in embryonic development. We also show that the Wnt/beta-catenin pathway is active and that Wnt3 is expressed in the hippocampal neurogenic niche. Overexpression of Wnt3 is sufficient to increase neurogenesis from AHPs in vitro and in vivo. By contrast, blockade of Wnt signalling reduces neurogenesis from AHPs in vitro and abolishes neurogenesis almost completely in vivo. Our data show that Wnt signalling is a principal regulator of adult hippocampal neurogenesis and provide evidence that Wnt proteins have a role in adult hippocampal function.
Asunto(s)
Hipocampo/citología , Hipocampo/metabolismo , Neuronas/citología , Neuronas/metabolismo , Transducción de Señal , Envejecimiento/fisiología , Animales , Astrocitos/citología , Astrocitos/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Células Madre/citología , Células Madre/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Proteína Wnt3RESUMEN
New cells are continuously generated from immature proliferating cells throughout adulthood in many organs, thereby contributing to the integrity of the tissue under physiological conditions and to repair following injury. In contrast, repair mechanisms in the adult central nervous system (CNS) have long been thought to be very limited. However, recent findings have clearly demonstrated that in restricted areas of the mammalian brain, new functional neurons are constantly generated from neural stem cells throughout life. Moreover, stem cells with the potential to give rise to new neurons reside in many different regions of the adult CNS. These findings raise the possibility that endogenous neural stem cells can be mobilized to replace dying neurons in neurodegenerative diseases. Indeed, recent reports have provided evidence that, in some injury models, limited neuronal replacement occurs in the CNS. Here, we summarize our current understanding of the mechanisms controlling adult neurogenesis and discuss their implications for the development of new strategies for the treatment of neurodegenerative diseases.