RESEARCH Open Accessβ-Amyloid triggers aberrant over-scaling ofhomeostatic synaptic plasticityJames Gilbert 1 , Shu Shu 2 , Xin Yang 2 , Youming Lu 2,5 , Ling-Qiang Zhu 3,5 and Heng-Ye Man 1,4,5*AbstractThe over-production of β-amyloid (Aβ) has been strongly correlated to neuronal dysfunction and altered synapticplasticity in Alzheimer’s disease (AD). Accordingly, it has been proposed that disrupted synaptic transmission andneuronal network instability underlie memory failure that is evident in the early phases of AD. Homeostatic synapticplasticity (HSP) serves to restrain neuronal activity within a physiological range. Therefore a disruption of thismechanism may lead to destabilization in synaptic and neural circuit function. Here, we report that during HSP byneuronal activity deprivation, application of Aβ results in an aberrant over-response of the up-regulation of AMPAreceptor (AMPAR)-mediated synaptic currents and cell-surface AMPAR expression. In the visual cortex, in vivo HSPinduced by visual deprivation shows a similar over-response following an Aβ local injection. Aβ increases theexpression of GluA2-lacking, calcium permeable AMPARs (CP-AMPARs), which are required for the initiation, but notmaintenance of HSP. Both GluA2-lacking and GluA2-containing AMPARs contribute to the Aβ-mediated over-scalingof HSP. We also find that Aβ induces the dissociation of HDAC1 from the miR124 transcription factor EVI1, leadingto an up-regulation of miR124 expression and increased amount of CP-AMPARs. Thus, via aberrant stimulation ofmiR124 expression and biogenesis of CP-AMPARs, Aβ is able to induce an over response in HSP. This Aβ-mediateddysregulation in homeostatic plasticity may play an important role in the pathogenesis of altered neural functionand memory deficits in the early stages of AD.Keywords: Homeostatic synaptic plasticity, Amyloid beta, Microrna 124, Calcium permeable AMPA receptorIntroductionAlzheimer’s Disease (AD) is characterized by deficits inlearning and memory with an eventual loss of highercognitive functions. Accumulation of β-amyloid (Aβ) inthe brain is a hallmark of AD and studies have demon-strated that Aβ can induce synapse dysregulation and al-tered neuronal activity [26, 32, 37, 54, 58]. Emergingevidence suggests that soluble Aβ oligomers adverselyaffect synaptic function, which eventually leads to thecognitive failure associated with AD [36, 43, 48, 58]. Akey neuropathobiological hallmark in early AD is the ab-errant regulation in synaptic function including AMPAreceptor (AMPAR) synaptic accumulation and synapticplasticity [7, 43]. In vitro studies performed in hippo-campal neurons have reported that application of Aβpeptides, at concentrations below neurotoxic levels, caninhibit LTP induction without affecting basal synaptictransmission [8, 9, 61]. A similar result was shown invivo, where cerebral injection of naturally secreted Aβcollected from cells expressing amyloid precursor pro-tein (APP) prevented the stable maintenance of LTP inthe hippocampal CA1 region [58]. In vivo injection ofAβ is reported to facilitate LTD and LTP reversal (depo-tentiation) in the CA1 region of the hippocampus [32].These studies have provided great insight into Hebbianplasticity in AD, however the role of Aβ in homeostaticsynaptic plasticity (HSP) remains largely unknown [29].A major function of HSP is to regulate neuronal activityin a negative feedback manner, thus maintaining neuronalactivity or synaptic function [15, 23] within a physiologicalrange after changes in network activity [6, 10, 55, 56].Under chronic suppression of neuronal activity, HSP isexpressed via an increase in synaptic expression ofAMPARs producing an up-scaling of AMPAR-mediatedminiature post-synaptic currents (mEPSCs). Whilemost studies show inactivity-induced synaptic scaling* Correspondence: hman@bu.edu1 Department of Biology, Boston University, Boston, MA, USA4 Department of Pharmacology & Experimental Therapeutics, BostonUniversity School of Medicine, Boston, MA, USAFull list of author information is available at the end of the article© The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Gilbert et al. Acta Neuropathologica Communications (2016) 4:131 DOI 10.1186/s40478-016-0398-0
