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      Understanding intellectual disability and autism spectrum disorders from common mouse models: synapses to behaviour

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          Abstract

          Normal brain development is highly dependent on the timely coordinated actions of genetic and environmental processes, and an aberration can lead to neurodevelopmental disorders (NDDs). Intellectual disability (ID) and autism spectrum disorders (ASDs) are a group of co-occurring NDDs that affect between 3% and 5% of the world population, thus presenting a great challenge to society. This problem calls for the need to understand the pathobiology of these disorders and to design new therapeutic strategies. One approach towards this has been the development of multiple analogous mouse models. This review discusses studies conducted in the mouse models of five major monogenic causes of ID and ASDs: Fmr1, Syngap1, Mecp2, Shank2/3 and Neuroligins/Neurnexins. These studies reveal that, despite having a diverse molecular origin, the effects of these mutations converge onto similar or related aetiological pathways, consequently giving rise to the typical phenotype of cognitive, social and emotional deficits that are characteristic of ID and ASDs. This convergence, therefore, highlights common pathological nodes that can be targeted for therapy. Other than conventional therapeutic strategies such as non-pharmacological corrective methods and symptomatic alleviation, multiple studies in mouse models have successfully proved the possibility of pharmacological and genetic therapy enabling functional recovery.

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          Most cited references 403

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          A synaptic model of memory: long-term potentiation in the hippocampus.

          Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.
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            The transcriptional landscape of the mammalian genome.

            This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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              Fate mapping analysis reveals that adult microglia derive from primitive macrophages.

              Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.
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                Author and article information

                Journal
                Open Biol
                Open Biol
                RSOB
                royopenbio
                Open Biology
                The Royal Society
                2046-2441
                June 2019
                12 June 2019
                12 June 2019
                : 9
                : 6
                Affiliations
                Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bengaluru 560 064, Karnataka, India
                Author notes
                [†]

                These authors contributed equally to this study.

                Article
                rsob180265
                10.1098/rsob.180265
                6597757
                31185809
                © 2019 The Authors.

                Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

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                June 2019

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