Major vault protein, a candidate gene in 16p11.2 microdeletion syndrome, is required for the homeostatic regulation of visual cortical plasticity.

J Neurosci. 2018 Mar 14;:

Authors: Ip JPK, Nagakura I, Petravicz J, Li K, Wiemer EAC, Sur M

Microdeletion of a region in chromosome 16p11.2 increases susceptibility to autism. Although this region contains exons of 29 genes, disrupting only a small segment of the region, which spans 5 genes, is sufficient to cause autistic traits. One candidate gene in this critical segment is MVP, which encodes for the major vault protein (MVP) that has been implicated in regulation of cellular transport mechanisms. MVP expression levels in MVP+/- mice closely phenocopy those of 16p11.2 mutant mice, suggesting that MVP+/- mice may serve as a model of MVP function in 16p11.2 microdeletion. Here we show that MVP regulates the homeostatic component of ocular dominance (OD) plasticity in primary visual cortex (V1). MVP+/- mice of both sexes show impairment in strengthening of open-eye responses after several days of monocular deprivation (MD) while closed-eye responses are weakened as normal, resulting in reduced overall OD plasticity. The frequency of mEPSCs in pyramidal neurons is decreased in MVP+/- mice after extended MD, suggesting a reduction of functional synapses. Correspondingly, upregulation of surface GluA1 AMPA receptors is reduced in MVP+/- mice after extended MD, and is accompanied by altered expression of STAT1 and phosphorylated ERK, which have been previously implicated in OD plasticity. Normalization of STAT1 levels by introducing STAT1 shRNA rescues surface GluA1 and open-eye responses, implicating STAT1 as a downstream effector of MVP. These findings demonstrate a specific role for MVP as a key molecule influencing the homeostatic component of activity-dependent synaptic plasticity, and potentially the corresponding phenotypes of 16p11.2 microdeletion syndrome.Significance StatementMajor vault protein (MVP), a candidate gene in 16p11.2 microdeletion syndrome, has been implicated in the regulation of several cellular processes including transport mechanisms and scaffold signaling. However, its role in brain function and plasticity remains unknown. In this study, we identified MVP as an important regulator of the homeostatic component of experience-dependent plasticity, via regulation of STAT1 and ERK signaling. This study helps reveal a new mechanism for an autism-related gene in brain function, and suggests a broader role for neuro-immune interactions in circuit level plasticity. Importantly, our findings might explain specific components of the pathophysiology of 16p11.2 microdeletion syndrome.

PMID: 29540554 [PubMed – as supplied by publisher]

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