title: β-Amyloid triggers aberrant over-scaling of homeostatic synaptic plasticity.
abstract: The over-production of β-amyloid (Aβ) has been strongly correlated to neuronal dysfunction and altered synaptic plasticity in Alzheimer's disease (AD). Accordingly, it has been proposed that disrupted synaptic transmission and neuronal network instability underlie memory failure that is evident in the early phases of AD. Homeostatic synaptic plasticity (HSP) serves to restrain neuronal activity within a physiological range. Therefore a disruption of this mechanism may lead to destabilization in synaptic and neural circuit function. Here, we report that during HSP by neuronal activity deprivation, application of Aβ results in an aberrant over-response of the up-regulation of AMPA receptor (AMPAR)-mediated synaptic currents and cell-surface AMPAR expression. In the visual cortex, in vivo HSP induced by visual deprivation shows a similar over-response following an Aβ local injection. Aβ increases the expression of GluA2-lacking, calcium permeable AMPARs (CP-AMPARs), which are required for the initiation, but not maintenance of HSP. Both GluA2-lacking and GluA2-containing AMPARs contribute to the Aβ-mediated over-scaling of HSP. We also find that Aβ induces the dissociation of HDAC1 from the miR124 transcription factor EVI1, leading to an up-regulation of miR124 expression and increased amount of CP-AMPARs. Thus, via aberrant stimulation of miR124 expression and biogenesis of CP-AMPARs, Aβ is able to induce an over response in HSP. This Aβ-mediated dysregulation in homeostatic plasticity may play an important role in the pathogenesis of altered neural function and memory deficits in the early stages of AD.
authors.affiliation: Department of Biology, Boston University, Boston, MA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Gilbert
authors.affiliation: Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Shu
authors.initials: S
authors.lastname: Shu
authors.affiliation: Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.|The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Youming
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.|The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Ling-Qiang
authors.initials: LQ
authors.lastname: Zhu
authors.affiliation: Department of Biology, Boston University, Boston, MA, USA. hman@bu.edu.|Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA. hman@bu.edu.|The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China. hman@bu.edu.
authors.forename: Heng-Ye
authors.identifier: 0000-0002-3530-3066
authors.initials: HY
authors.lastname: Man
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012683:Sensory Deprivation / Q000502:physiology; D014793:Visual Cortex / Q000378:metabolism / Q000473:pathology; D014796:Visual Perception / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D000074008:MDS1 and EVI1 Complex Locus Protein; C548144:MIRN124 microRNA, rat; C000610524:Mecom protein, rat; D035683:MicroRNAs; D018091:Receptors, AMPA; D012097:Repressor Proteins; C515890:Hdac1 protein, rat; D056284:Histone Deacetylase 1
keywords: Amyloid beta; Calcium permeable AMPA receptor; Homeostatic synaptic plasticity; Microrna 124