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      The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes

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          Abstract

          Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism. Formalin-fixed brain hemispheres of 13 autistic (4–60 years of age) and 14 age-matched control subjects were embedded in celloidin and cut into 200-μm-thick coronal sections, which were stained with cresyl violet and used for neuropathological evaluation. Thickening of the subependymal cell layer in two brains and subependymal nodular dysplasia in one brain is indicative of active neurogenesis in two autistic children. Subcortical, periventricular, hippocampal and cerebellar heterotopias detected in the brains of four autistic subjects (31%) reflect abnormal neuronal migration. Multifocal cerebral dysplasia resulted in local distortion of the cytoarchitecture of the neocortex in four brains (31%), of the entorhinal cortex in two brains (15%), of the cornu Ammonis in four brains and of the dentate gyrus in two brains. Cerebellar flocculonodular dysplasia detected in six subjects (46%), focal dysplasia in the vermis in one case, and hypoplasia in one subject indicate local failure of cerebellar development in 62% of autistic subjects. Detection of flocculonodular dysplasia in only one control subject and of a broad spectrum of focal qualitative neuropathological developmental changes in 12 of 13 examined brains of autistic subjects (92%) reflects multiregional dysregulation of neurogenesis, neuronal migration and maturation in autism, which may contribute to the heterogeneity of the clinical phenotype.

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          Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.

          Recent studies suggest that stress-induced atrophy and loss of hippocampal neurons may contribute to the pathophysiology of depression. The aim of this study was to investigate the effect of antidepressants on hippocampal neurogenesis in the adult rat, using the thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. Our studies demonstrate that chronic antidepressant treatment significantly increases the number of BrdU-labeled cells in the dentate gyrus and hilus of the hippocampus. Administration of several different classes of antidepressant, but not non-antidepressant, agents was found to increase BrdU-labeled cell number, indicating that this is a common and selective action of antidepressants. In addition, upregulation of the number of BrdU-labeled cells is observed after chronic, but not acute, treatment, consistent with the time course for the therapeutic action of antidepressants. Additional studies demonstrated that antidepressant treatment increases the proliferation of hippocampal cells and that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. These findings raise the possibility that increased cell proliferation and increased neuronal number may be a mechanism by which antidepressant treatment overcomes the stress-induced atrophy and loss of hippocampal neurons and may contribute to the therapeutic actions of antidepressant treatment.
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            Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

            Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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              Control of mental activities by internal models in the cerebellum.

               Masao ITO (2008)
              The intricate neuronal circuitry of the cerebellum is thought to encode internal models that reproduce the dynamic properties of body parts. These models are essential for controlling the movement of these body parts: they allow the brain to precisely control the movement without the need for sensory feedback. It is thought that the cerebellum might also encode internal models that reproduce the essential properties of mental representations in the cerebral cortex. This hypothesis suggests a possible mechanism by which intuition and implicit thought might function and explains some of the symptoms that are exhibited by psychiatric patients. This article examines the conceptual bases and experimental evidence for this hypothesis.
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                Author and article information

                Contributors
                +1-718-4945231 , +1-718-9824856 , jerzy.wegiel@omr.state.ny.us
                Journal
                Acta Neuropathol
                Acta Neuropathologica
                Springer-Verlag (Berlin/Heidelberg )
                0001-6322
                1432-0533
                3 March 2010
                3 March 2010
                June 2010
                : 119
                : 6
                : 755-770
                Affiliations
                [1 ]Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities (IBR), 1050 Forest Hill Road, Staten Island, NY 10314 USA
                [2 ]Department of Neurology, New York University School of Medicine, New York, NY USA
                [3 ]Department of Pathology, New York University School of Medicine, New York, NY USA
                [4 ]Department of Psychiatry, New York University School of Medicine, New York, NY USA
                [5 ]Department of Neurochemistry, IBR, Staten Island, NY USA
                [6 ]Department of Neuropathology, Institute of Psychiatry and Neurology, Warsaw, Poland
                [7 ]Department of Psychology, IBR, Staten Island, NY USA
                [8 ]Department of Human Genetics, IBR, Staten Island, NY USA
                [9 ]Corinthian Diagnostic Radiology, New York, NY USA
                [10 ]Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY USA
                Article
                655
                10.1007/s00401-010-0655-4
                2869041
                20198484
                © The Author(s) 2010
                Categories
                Original Paper
                Custom metadata
                © Springer-Verlag 2010

                Neurology

                developmental neuropathology, dysplasia, heterotopia, subependymal nodular dysplasia, autism

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