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Major Vault Protein, a Candidate Gene in 16P11.2 Microdeletion Syndrome, Is Required for the Homeostatic Regulation of Visual Cortical Plasticity

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Major Vault Protein, a Candidate Gene in 16P11.2 Microdeletion Syndrome, Is Required for the Homeostatic Regulation of Visual Cortical Plasticity This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Development/Plasticity/Repair Major vault protein, a candidate gene in 16p11.2 microdeletion syndrome, is required for the homeostatic regulation of visual cortical plasticity Jacque P K Ip1, Ikue Nagakura1, Jeremy Petravicz1, Keji Li1, Erik A.C. Wiemer2 and Mriganka Sur1 1Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139 USA 2Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands DOI: 10.1523/JNEUROSCI.2034-17.2018 Received: 18 July 2017 Revised: 17 February 2018 Accepted: 2 March 2018 Published: 14 March 2018 Author contributions: K.L. edited the paper; J.P.K.I., I.N., and M.S. designed research; J.P.K.I., I.N., J.P., and K.L. performed research; E.A.W. contributed unpublished reagents/analytic tools; J.P.K.I., I.N., J.P., and K.L. analyzed data; J.P.K.I., I.N., and M.S. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. This work was supported by Human Frontier Science Program Long-Term Fellowship (J.P.K.I), NIH grants MH085802 and EY007023 (M.S.), Simons Postdoctoral Fellowship (I.N.) and the Simons Foundation Autism Research Initiative through the Simons Center for the Social Brain, MIT (M.S.). We thank Bess Rosen for technical assistance. Correspondence: Mriganka Sur ([email protected]) Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139 USA Cite as: J. Neurosci ; 10.1523/JNEUROSCI.2034-17.2018 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2018 the authors 1 Title: Major vault protein, a candidate gene in 2 16p11.2 microdeletion syndrome, is required for the 3 homeostatic regulation of visual cortical plasticity 4 5 Abbreviated title: Major vault protein in cortical plasticity 6 7 8 Authors: Jacque P K Ip1*, Ikue Nagakura1*, Jeremy Petravicz1, Keji Li1, Erik A.C. 9 Wiemer2 & Mriganka Sur1 10 11 Affiliations: 12 1Department of Brain and Cognitive Sciences, Picower Institute for Learning and 13 Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 14 Cambridge, Massachusetts 02139 USA 15 2Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus 16 University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The 17 Netherlands 18 19 * These authors contributed equally to this work. 20 21 Correspondence: 22 Mriganka Sur ([email protected]) 23 Department of Brain and Cognitive Sciences, Picower Institute for Learning and 24 Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 25 Cambridge, Massachusetts 02139 USA 26 27 28 Acknowledgements: 29 This work was supported by Human Frontier Science Program Long-Term 30 Fellowship (J.P.K.I), NIH grants MH085802 and EY007023 (M.S.), Simons 31 Postdoctoral Fellowship (I.N.) and the Simons Foundation Autism Research 32 Initiative through the Simons Center for the Social Brain, MIT (M.S.). We thank 33 Bess Rosen for technical assistance. 34 35 Conflict of Interest: 36 The authors declare no competing financial interests. 37 38 Number of pages: 32 39 Number of figures: 5 40 Number of tables, multimedia and 3D models: 0 41 Number of words for Abstract: 249 42 Number of words for Introduction: 649 43 Number of words for Discussion: 1009 44 45 1 46 Abstract 47 48 Microdeletion of a region in chromosome 16p11.2 increases susceptibility to 49 autism. Although this region contains exons of 29 genes, disrupting only a small 50 segment of the region, which spans 5 genes, is sufficient to cause autistic traits. 51 One candidate gene in this critical segment is MVP, which encodes for the major 52 vault protein (MVP) that has been implicated in regulation of cellular transport 53 mechanisms. MVP expression levels in MVP+/- mice closely phenocopy those of 54 16p11.2 mutant mice, suggesting that MVP+/- mice may serve as a model of MVP 55 function in 16p11.2 microdeletion. Here we show that MVP regulates the 56 homeostatic component of ocular dominance (OD) plasticity in primary visual 57 cortex (V1). MVP+/- mice of both sexes show impairment in strengthening of 58 open-eye responses after several days of monocular deprivation (MD) while 59 closed-eye responses are weakened as normal, resulting in reduced overall OD 60 plasticity. The frequency of mEPSCs in pyramidal neurons is decreased in 61 MVP+/- mice after extended MD, suggesting a reduction of functional synapses. 62 Correspondingly, upregulation of surface GluA1 AMPA receptors is reduced in 63 MVP+/- mice after extended MD, and is accompanied by altered expression of 64 STAT1 and phosphorylated ERK, which have been previously implicated in OD 65 plasticity. Normalization of STAT1 levels by introducing STAT1 shRNA rescues 66 surface GluA1 and open-eye responses, implicating STAT1 as a downstream 67 effector of MVP. These findings demonstrate a specific role for MVP as a key 68 molecule influencing the homeostatic component of activity-dependent synaptic 2 69 plasticity, and potentially the corresponding phenotypes of 16p11.2 microdeletion 70 syndrome. 71 72 Significance Statement 73 74 Major vault protein (MVP), a candidate gene in 16p11.2 microdeletion syndrome, 75 has been implicated in the regulation of several cellular processes including 76 transport mechanisms and scaffold signaling. However, its role in brain function 77 and plasticity remains unknown. In this study, we identified MVP as an important 78 regulator of the homeostatic component of experience-dependent plasticity, via 79 regulation of STAT1 and ERK signaling. This study helps reveal a new 80 mechanism for an autism-related gene in brain function, and suggests a broader 81 role for neuro-immune interactions in circuit level plasticity. Importantly, our 82 findings might explain specific components of the pathophysiology of 16p11.2 83 microdeletion syndrome. 84 3 85 Introduction 86 87 Microdeletion of a region in chromosome 16p11.2 increases susceptibility to 88 autism spectrum disorder (ASD) and accounts for up to 1% of the ASD 89 population (Malhotra and Sebat, 2012). Patients carrying this microdeletion 90 exhibit cognitive disability, language delay, ASD and seizures (Fernandez et al., 91 2010; Hanson et al., 2015). Deletion of the entire 16p11.2 region in mice leads to 92 diverse phenotypes, including hyperactivity, deficits in contextual conditioning 93 and novel object recognition (Horev et al., 2011; Portmann et al., 2014; Tian et 94 al., 2015). Although 16p11.2 microdeletion commonly leads to haploinsufficiency 95 of 29 genes, disrupting only a small segment of this region, which spans 5 genes, 96 is sufficient to cause autistic traits (Crepel et al., 2011). One candidate gene in 97 this critical segment is MVP, which encodes for the major vault protein (MVP). 98 99 MVP is the main structural component of large cellular ribonucleoparticles termed 100 vaults. Vaults, weighing 13 MDa, are considered to be involved in 101 nucleocytoplasmic transport (Berger et al., 2009). MVP, also known as lung 102 resistance-related protein (LRP), is upregulated in a number of tumors and 103 implicated in drug resistance (Mossink et al., 2003b; Berger et al., 2009). 104 However, very little is known about its function in the central nervous system. 105 MVP is required for brain development and synapse formation in invertebrate 106 species (Paspalas et al., 2009; Blaker-Lee et al., 2012; Pan et al., 2013). It has 107 been suggested that MVP may be a regulator of multiple intracellular signaling 4 108 pathways, several of which are known to mediate aspects of synaptic plasticity 109 and function (Kolli et al., 2004; Chung and Eng, 2005; Kim et al., 2006; Steiner et 110 al., 2006). 111 112 Many genes that confer risk for ASD affect synaptic and circuit plasticity during 113 development (Sahin and Sur, 2015). Ocular dominance (OD) plasticity in the 114 primary visual cortex (V1), particularly during a developmental critical period, is a 115 well-established model for understanding experience-dependent functional 116 changes in cortical circuits (Hubel and Wiesel, 1970; Gordon and Stryker, 1996; 117 Bear, 2003; Hensch, 2005). Monocular deprivation (MD) by suturing the eyelids 118 of one eye leads to physiological reduction of cortical responses to the deprived 119 (closed) eye, subsequently followed by strengthening of responses to the non- 120 deprived (open) eye (Frenkel and Bear, 2004). Despite no change in visual drive, 121 the strengthening of the non-deprived eye represents an internally driven 122 homeostatic response resulting from a change in eye-specific cortical drive 123 (Turrigiano and Nelson, 2004; Espinosa and Stryker, 2012; Cooke and Bear, 124 2014). Homeostatic synaptic plasticity is particularly pronounced in developing 125 cortical neurons in vitro (Gainey et al., 2009; Qiu et al., 2012). In V1, activity- 126 induced changes in neurons involve feedforward, Hebbian changes together with 127 feedback, homeostatic changes, which are mediated by key molecular pathways 128 (Tropea et al., 2009b; Sur et al., 2013; Pulimood et al., 2017). Deficits in plasticity 129 due to alterations in ASD genes may fundamentally involve deficits in 130 homeostatic mechanisms of plasticity (Nelson and Valakh, 2015). 5 131 132 Here, we investigated the role of MVP in experience-dependent cortical plasticity 133 in mouse V1. We found that MVP heterozygous deletion (MVP+/-) mice show 134 impairment in strengthening of open-eye responses after several days of MD 135 while closed-eye responses were weakened as normal, resulting in reduced 136 overall OD plasticity.
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