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      The Intense World Theory – A Unifying Theory of the Neurobiology of Autism

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          Abstract

          Autism covers a wide spectrum of disorders for which there are many views, hypotheses and theories. Here we propose a unifying theory of autism, the Intense World Theory. The proposed neuropathology is hyper-functioning of local neural microcircuits, best characterized by hyper-reactivity and hyper-plasticity. Such hyper-functional microcircuits are speculated to become autonomous and memory trapped leading to the core cognitive consequences of hyper-perception, hyper-attention, hyper-memory and hyper-emotionality. The theory is centered on the neocortex and the amygdala, but could potentially be applied to all brain regions. The severity on each axis depends on the severity of the molecular syndrome expressed in different brain regions, which could uniquely shape the repertoire of symptoms of an autistic child. The progression of the disorder is proposed to be driven by overly strong reactions to experiences that drive the brain to a hyper-preference and overly selective state, which becomes more extreme with each new experience and may be particularly accelerated by emotionally charged experiences and trauma. This may lead to obsessively detailed information processing of fragments of the world and an involuntarily and systematic decoupling of the autist from what becomes a painfully intense world. The autistic is proposed to become trapped in a limited, but highly secure internal world with minimal extremes and surprises. We present the key studies that support this theory of autism, show how this theory can better explain past findings, and how it could resolve apparently conflicting data and interpretations. The theory also makes further predictions from the molecular to the behavioral levels, provides a treatment strategy and presents its own falsifying hypothesis.

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          Most cited references 282

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          Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.

          Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.
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            The attention system of the human brain.

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              Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.

              Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.
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                Author and article information

                Journal
                Front Hum Neurosci
                Front. Hum. Neurosci.
                Frontiers in Human Neuroscience
                Frontiers Research Foundation
                1662-5161
                16 August 2010
                21 December 2010
                2010
                : 4
                Affiliations
                1Laboratory of Neural Microcircuits, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne Lausanne, Switzerland
                Author notes

                Edited by: Silvia A. Bunge, University of California Berkeley, USA

                Reviewed by: Matthew K. Belmonte, National Brain Research Centre Manesar, India; Egidio D'Angelo, University of Pavia, Italy

                *Correspondence: Kamila Markram, Laboratory of Neural Microcircuits, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Building AAB - Office 201 - Station 15, 1015 Lausanne, Switzerland. e-mail: kamila.markram@ 123456epfl.ch
                Article
                10.3389/fnhum.2010.00224
                3010743
                21191475
                Copyright © 2010 Markram and Markram.

                This is an open-access article subject to an exclusive license agreement between the authors and the Frontiers Research Foundation, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are credited.

                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 329, Pages: 29, Words: 29234
                Categories
                Neuroscience
                Review Article

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