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      A Role for Synaptic Zinc in ProSAP/Shank PSD Scaffold Malformation in Autism Spectrum Disorders

      1 , 2

      Developmental Neurobiology

      BlackWell Publishing Ltd

      Shank3, Shank2, Phelan McDermid Syndrome, 22q13, Zn2+

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          The establishment and maintenance of synaptic contacts as well as synaptic plasticity are crucial factors for normal brain function. The functional properties of a synapse are largely dependent on the molecular setup of synaptic proteins. Multidomain proteins of the ProSAP/Shank family act as major organizing scaffolding elements of the postsynaptic density (PSD). Interestingly, ProSAP/Shank proteins at glutamatergic synapses have been linked to a variety of Autism Spectrum Disorders (ASDs) including Phelan McDermid Syndrome, and deregulation of ProSAP/Shank has been reported in Alzheimer's disease. Although the precise molecular mechanism of the dysfunction of these proteins remains unclear, an emerging model is that mutations or deletions impair neuronal circuitry by disrupting the formation, plasticity and maturation of glutamatergic synapses. Several PSD proteins associated with ASDs are part of a complex centered around ProSAP/Shank proteins and many ProSAP/Shank interaction partners play a role in signaling within dendritic spines. Interfering with any one of the members of this signaling complex might change the output and drive the system towards synaptic dysfunction. Based on recent data, it is possible that the concerted action of ProSAP/Shank and Zn 2+ is essential for the structural integrity of the PSD. This interplay might regulate postsynaptic receptor composition, but also transsynaptic signaling. It might be possible that environmental factors like nutritional Zn 2+ status or metal ion homeostasis in general intersect with this distinct pathway centered around ProSAP/Shank proteins and the deregulation of any of these two factors may lead to ASDs.

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          Most cited references 75

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          Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

          Evidence for the etiology of autism spectrum disorders (ASD) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity 1,2 . We sequenced the exomes of 20 sporadic cases of ASD and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, of which 11 were protein-altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4/20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A, and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 mutation and provide functional support for a multihit model for disease risk 3 . Our results demonstrate that trio-based exome sequencing is a powerful approach for identifying novel candidate genes for ASD and suggest that de novo mutations may contribute substantially to the genetic risk for ASD.
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            Long-term potentiation and memory.

             M A Lynch (2004)
            One of the most significant challenges in neuroscience is to identify the cellular and molecular processes that underlie learning and memory formation. The past decade has seen remarkable progress in understanding changes that accompany certain forms of acquisition and recall, particularly those forms which require activation of afferent pathways in the hippocampus. This progress can be attributed to a number of factors including well-characterized animal models, well-defined probes for analysis of cell signaling events and changes in gene transcription, and technology which has allowed gene knockout and overexpression in cells and animals. Of the several animal models used in identifying the changes which accompany plasticity in synaptic connections, long-term potentiation (LTP) has received most attention, and although it is not yet clear whether the changes that underlie maintenance of LTP also underlie memory consolidation, significant advances have been made in understanding cell signaling events that contribute to this form of synaptic plasticity. In this review, emphasis is focused on analysis of changes that occur after learning, especially spatial learning, and LTP and the value of assessing these changes in parallel is discussed. The effect of different stressors on spatial learning/memory and LTP is emphasized, and the review concludes with a brief analysis of the contribution of studies, in which transgenic animals were used, to the literature on memory/learning and LTP.
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              The neurobiology of zinc in health and disease.

              The use of zinc in medicinal skin cream was mentioned in Egyptian papyri from 2000 BC (for example, the Smith Papyrus), and zinc has apparently been used fairly steadily throughout Roman and modern times (for example, as the American lotion named for its zinc ore, 'Calamine'). It is, therefore, somewhat ironic that zinc is a relatively late addition to the pantheon of signal ions in biology and medicine. However, the number of biological functions, health implications and pharmacological targets that are emerging for zinc indicate that it might turn out to be 'the calcium of the twenty-first century'.

                Author and article information

                Dev Neurobiol
                Dev Neurobiol
                Developmental Neurobiology
                BlackWell Publishing Ltd (Oxford, UK )
                February 2014
                11 September 2013
                : 74
                : 2
                : 136-146
                [1 ]Neurology Department, WG Molecular Analysis of Synaptopathies, Neurocenter of Ulm University Ulm, Germany
                [2 ]Institute for Anatomy and Cell Biology, Ulm University Ulm, Germany
                Author notes
                Correpondence to: A.M. Grabrucker ( andreas.grabrucker@ 123456uni-ulm.de ).
                Copyright © 2013 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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