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      ASD-Associated De Novo Mutations in Five Actin Regulators Show Both Shared and Distinct Defects in Dendritic Spines and Inhibitory Synapses in Cultured Hippocampal Neurons

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          Abstract

          Many actin cytoskeleton-regulating proteins control dendritic spine morphology and density, which are cellular features often altered in autism spectrum disorder (ASD). Recent studies using animal models show that autism-related behavior can be rescued by either manipulating actin regulators or by reversing dendritic spine density or morphology. Based on these studies, the actin cytoskeleton is a potential target pathway for developing new ASD treatments. Thus, it is important to understand how different ASD-associated actin regulators contribute to the regulation of dendritic spines and how ASD-associated mutations modulate this regulation. For this study, we selected five genes encoding different actin-regulating proteins and induced ASD-associated de novo missense mutations in these proteins. We assessed the functionality of the wild-type and mutated proteins by analyzing their subcellular localization, and by analyzing the dendritic spine phenotypes induced by the expression of these proteins. As the imbalance between excitation and inhibition has been suggested to have a central role in ASD, we additionally evaluated the density, size and subcellular localization of inhibitory synapses. Common for all the proteins studied was the enrichment in dendritic spines. ASD-associated mutations induced changes in the localization of α-actinin-4, which localized less to dendritic spines, and for SWAP-70 and SrGAP3, which localized more to dendritic spines. Among the wild-type proteins studied, only α-actinin-4 expression caused a significant change in dendritic spine morphology by increasing the mushroom spine density and decreasing thin spine density. We hypothesized that mutations associated with ASD shift dendritic spine morphology from mushroom to thin spines. An M554V mutation in α-actinin-4 ( ACTN4) resulted in the expected shift in dendritic spine morphology by increasing the density of thin spines. In addition, we observed a trend toward higher thin spine density with mutations in myosin IXb and SWAP-70. Myosin IIb and myosin IXb expression increased the proportion of inhibitory synapses in spines. The expression of mutated myosin IIb (Y265C), SrGAP3 (E469K), and SWAP-70 (L544F) induced variable changes in inhibitory synapses.

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          Most cited references46

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          De novo gene disruptions in children on the autistic spectrum.

          Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Transient and persistent dendritic spines in the neocortex in vivo.

            Dendritic spines were imaged over days to months in the apical tufts of neocortical pyramidal neurons (layers 5 and 2/3) in vivo. A fraction of thin spines appeared and disappeared over a few days, while most thick spines persisted for months. In the somatosensory cortex, from postnatal day (PND) 16 to PND 25 spine retractions exceeded additions, resulting in a net loss of spines. The fraction of persistent spines (lifetime > or = 8 days) grew gradually during development and into adulthood (PND 16-25, 35%; PND 35-80, 54%; PND 80-120, 66%; PND 175-225, 73%), providing evidence that synaptic circuits continue to stabilize even in the adult brain, long after the closure of known critical periods. In 6-month-old mice, spines turn over more slowly in visual compared to somatosensory cortex, possibly reflecting differences in the capacity for experience-dependent plasticity in these brain regions.
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              Structure-stability-function relationships of dendritic spines.

              Dendritic spines, which receive most of the excitatory synaptic input in the cerebral cortex, are heterogeneous with regard to their structure, stability and function. Spines with large heads are stable, express large numbers of AMPA-type glutamate receptors, and contribute to strong synaptic connections. By contrast, spines with small heads are motile and unstable and contribute to weak or silent synaptic connections. Their structure-stability-function relationships suggest that large and small spines are "memory spines" and "learning spines", respectively. Given that turnover of glutamate receptors is rapid, spine structure and the underlying organization of the actin cytoskeleton are likely to be major determinants of fast synaptic transmission and, therefore, are likely to provide a physical basis for memory in cortical neuronal networks. Characterization of supramolecular complexes responsible for synaptic memory and learning is key to the understanding of brain function and disease.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                03 August 2018
                2018
                : 12
                Affiliations
                [1] 1Minerva Foundation Institute for Medical Research , Helsinki, Finland
                [2] 2HiLIFE, University of Helsinki , Helsinki, Finland
                [3] 3Neuroscience Center, University of Helsinki , Helsinki, Finland
                [4] 4Institute of Biotechnology, University of Helsinki , Helsinki, Finland
                Author notes

                Edited by: Monica Mendes Sousa, i3S, Instituto de Investigação e Inovação em Saúde, Portugal

                Reviewed by: Marco Rust, Philipps University of Marburg, Germany; Jaewon Ko, Daegu Gyeongbuk Institute of Science and Technology (DGIST), South Korea; Maurizio Giustetto, Università degli Studi di Torino, Italy

                *Correspondence: Pirta Hotulainen pirta.hotulainen@ 123456helsinki.fi
                Article
                10.3389/fncel.2018.00217
                6085419
                47c87d9d-8ba1-4d95-89cc-6f50cd19875e
                Copyright © 2018 Hlushchenko, Khanal, Abouelezz, Paavilainen and Hotulainen.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 14, Tables: 2, Equations: 0, References: 72, Pages: 23, Words: 12942
                Funding
                Funded by: Instrumentariumin Tiedesäätiö 10.13039/501100008413
                Funded by: Alfred Kordelinin Säätiö 10.13039/100008969
                Funded by: Academy of Finland 10.13039/501100002341
                Award ID: 289737
                Funded by: Sigrid Juséliuksen Säätiö 10.13039/501100006306
                Categories
                Neuroscience
                Original Research

                Neurosciences
                autism spectrum disorder,actin cytoskeleton,dendritic spines,inhibitory synapses,de novo point mutations

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