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      Altered proliferation and networks in neural cells derived from idiopathic autistic individuals.

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          Abstract

          Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells, neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation because of dysregulation of a β-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by insulin growth factor 1 (IGF-1), a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.

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          A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells.

          Maria C. N. Marchetto, Cassiano Carromeu, Allan Acab … (2010)
          Autism spectrum disorders (ASD) are complex neurodevelopmental diseases in which different combinations of genetic mutations may contribute to the phenotype. Using Rett syndrome (RTT) as an ASD genetic model, we developed a culture system using induced pluripotent stem cells (iPSCs) from RTT patients' fibroblasts. RTT patients' iPSCs are able to undergo X-inactivation and generate functional neurons. Neurons derived from RTT-iPSCs had fewer synapses, reduced spine density, smaller soma size, altered calcium signaling and electrophysiological defects when compared to controls. Our data uncovered early alterations in developing human RTT neurons. Finally, we used RTT neurons to test the effects of drugs in rescuing synaptic defects. Our data provide evidence of an unexplored developmental window, before disease onset, in RTT syndrome where potential therapies could be successfully employed. Our model recapitulates early stages of a human neurodevelopmental disease and represents a promising cellular tool for drug screening, diagnosis and personalized treatment. Copyright © 2010 Elsevier Inc. All rights reserved.
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            Functional organization of the transcriptome in human brain.

            Michael Oldham, Genevieve Konopka, Kazuya Iwamoto … (2008)
            The enormous complexity of the human brain ultimately derives from a finite set of molecular instructions encoded in the human genome. These instructions can be directly studied by exploring the organization of the brain's transcriptome through systematic analysis of gene coexpression relationships. We analyzed gene coexpression relationships in microarray data generated from specific human brain regions and identified modules of coexpressed genes that correspond to neurons, oligodendrocytes, astrocytes and microglia. These modules provide an initial description of the transcriptional programs that distinguish the major cell classes of the human brain and indicate that cell type-specific information can be obtained from whole brain tissue without isolating homogeneous populations of cells. Other modules corresponded to additional cell types, organelles, synaptic function, gender differences and the subventricular neurogenic niche. We found that subventricular zone astrocytes, which are thought to function as neural stem cells in adults, have a distinct gene expression pattern relative to protoplasmic astrocytes. Our findings provide a new foundation for neurogenetic inquiries by revealing a robust and previously unrecognized organization to the human brain transcriptome.
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              Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study.

              E Courchesne, C. Karns, H Davis … (2001)
              To quantify developmental abnormalities in cerebral and cerebellar volume in autism. The authors studied 60 autistic and 52 normal boys (age, 2 to 16 years) using MRI. Thirty autistic boys were diagnosed and scanned when 5 years or older. The other 30 were scanned when 2 through 4 years of age and then diagnosed with autism at least 2.5 years later, at an age when the diagnosis of autism is more reliable. Neonatal head circumferences from clinical records were available for 14 of 15 autistic 2- to 5-year-olds and, on average, were normal (35.1 +/- 1.3 cm versus clinical norms: 34.6 +/- 1.6 cm), indicative of normal overall brain volume at birth; one measure was above the 95th percentile. By ages 2 to 4 years, 90% of autistic boys had a brain volume larger than normal average, and 37% met criteria for developmental macrencephaly. Autistic 2- to 3-year-olds had more cerebral (18%) and cerebellar (39%) white matter, and more cerebral cortical gray matter (12%) than normal, whereas older autistic children and adolescents did not have such enlarged gray and white matter volumes. In the cerebellum, autistic boys had less gray matter, smaller ratio of gray to white matter, and smaller vermis lobules VI-VII than normal controls. Abnormal regulation of brain growth in autism results in early overgrowth followed by abnormally slowed growth. Hyperplasia was present in cerebral gray matter and cerebral and cerebellar white matter in early life in patients with autism.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Mol. Psychiatry
                Title: Molecular psychiatry
                Publisher: Springer Nature
                ISSN (Electronic): 1476-5578
                ISSN (Print): 1359-4184
                Publication date (Electronic): Jun 2017
                Volume: 22
                Issue: 6
                Affiliations
                [1 ] Laboratory of Genetics, The Salk Institute, La Jolla, CA, USA.
                [2 ] Department of Pediatrics, Institute for Human Genetics, University of California, San Francisco, CA, USA.
                [3 ] Program in Neurogenetics, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
                [4 ] Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular and Molecular Medicine, Stem Cell Program, University of California, San Diego, La Jolla, CA, USA.
                [5 ] Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
                [6 ] Department of Obstetrics and Surgery, Center for Cellular and Molecular Therapy, University of São Paulo, São Paulo, Brazil.
                [7 ] Department of Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
                [8 ] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [9 ] Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
                Article
                Publisher Item ID: mp201695 Mid ID: NIHMS784819
                DOI: 10.1038/mp.2016.95
                PMC ID: 5215991
                PubMed ID: 27378147
                SO-VID: c58f4df6-3a4e-49ee-8048-0b645fcdd903
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