Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus

Whitcomb, Daniel J.; Hogg, Ellen L.; Regan, Philip; Piers, Thomas M.; Narayan, Priyanka; Whitehead, Garry; Winters, Bryony L.; Kim, Dong-Hyun; Kim, Eunjoon; George-Hyslop, Peter St; Klenerman, David; Collingridge, Graham L.; Jo, Jihoon; Cho, Kwangwook

doi:10.1038/srep10934

Cited by 89 publications

(82 citation statements)

References 73 publications

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“…There is a growing body of evidence implicating CP-AMPARs during the onset of synaptic pathology in neurological disorders [21, 35, 47, 60]. Previous analyses of hippocampal postsynaptic density fractions from human AD patients showed an increase in GluA1 levels compared to healthy controls, whereas no changes in NMDAR subunit expression were observed [41], suggesting a selective increase in GluA1-containing receptors in the hippocampus of AD patients.…”

Section: Discussionmentioning

confidence: 99%

β-Amyloid triggers aberrant over-scaling of homeostatic synaptic plasticity

Gilbert

Shu

Yang

et al. 2016

acta neuropathol commun

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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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0398-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

β-Amyloid triggers aberrant over-scaling of homeostatic synaptic plasticity

Gilbert

Shu

Yang

et al. 2016

acta neuropathol commun

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“…Conversely, intracellular application of oligomerised Aβ causes an acute increase in AMPAR-mediated synaptic responses, which requires PKA phosphorylation of S845 in GluA1. Ablation of GluA1, but not GluA2, prevents this increase, consistent with intracellular Aβ causing an enhancement of synaptic CP-AMPAR number and consequent excitotoxicity 146 . The selective loss of GluA2-containing AMPARs and the subsequent increase in intracellular Ca 2+ due to the expression of CP-AMPARs is implicated in the pathology of many other diseases.…”

Section: Ampar Subunits and Diseasementioning

confidence: 74%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. PrefaceAMPARs are assemblies of four core subunits, GluA1-4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity, and in response to neuronal stress in disease. Recently, the subunit-dependence of AMPAR trafficking has been questioned leading to a reappraisal of the field. Here we review what is known, uncertain, conjectured and unknown about the roles of individual subunits and how they impact on AMPAR assembly, trafficking and function under normal and pathological conditions. IntroductionAMPA receptors (AMPARs) are a subtype of ionotropic glutamate receptors that are the 'work-horses' of fast excitatory neurotransmission in the CNS. Developmentallyand activity-regulated changes in the numbers and properties of AMPARs localized at the postsynaptic membrane are essential for excitatory synapse formation, stabilization, synaptic plasticity and neural circuit formation. Consequently, the logistics of the delivery, retention and removal of individual AMPARs with defined subunit compositions at specific synapses is highly complex. A typical cortical or hippocampal pyramidal neuron contains on the order of 10,000 synapses and the AMPARs at each synapse are independently and dynamically regulated in response to developmental cues, synaptic activity and environmental stresses. Furthermore, defects in the processes that control AMPAR assembly, trafficking and synaptic expression are intimately linked to psychiatric and neurological conditions, and also with cognitive decline in neurodegenerative diseases. Remarkable progress has been achieved in understanding how AMPAR trafficking, is orchestrated by a large array of AMPAR interacting proteins. These studies have established a set of hierarchical subunit-specific rules that control AMPAR trafficking under basal and activity-dependent conditions. Furthermore, there has been a growing appreciation that subunit composition can tune the properties of AMPARs to specific conditions. Nonetheless, how AMPARs comprising different subunits are differentially trafficked to control synaptic development, stabilisation and plasticity is a key unanswered question. Here, we provide an overview of the current state of knowledge of subunit-specific AMPAR trafficking and outline what we believe to be the key unresolved questions in the field. 2 Subunit-specific traffickingMost AMPARs are heterotetrameric assemblies of combinations of the subunits GluA1, GluA2, GluA3 and GluA4. AMPARs are expressed in both neurons and glia throughout the CNS 1 and have a turnover time of between 10 hours and 2 days depending on the type of neuron and developmental stage 2,3 . Each subunit has an identical membrane topology and c...

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“…They are tetramers, often heterotetramers, made up of four subunits, called GluR1–4 or GluA1–4 [45]. GluR1 and GluR2 are vital in the normal functioning of the human brain, and also have roles in neurological diseases, such as Alzheimer’s disease [46,47] and drug addiction [48,49]. Evidence for AMPA receptor expression in iNGN synapses was confirmed by the kinetic properties of mEPSCs (Fig 6 and Table 1), inhibitor studies (Fig 7), and by immunocytochemistry using antibodies against GluR1 and GluR2 (S4 Fig and S5 Fig).…”

Section: Discussionmentioning

confidence: 99%

Functional Maturation of Human Stem Cell-Derived Neurons in Long-Term Cultures

et al. 2017

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Differentiated neurons can be rapidly acquired, within days, by inducing stem cells to express neurogenic transcription factors. We developed a protocol to maintain long-term cultures of human neurons, called iNGNs, which are obtained by inducing Neurogenin-1 and Neurogenin-2 expression in induced pluripotent stem cells. We followed the functional development of iNGNs over months and they showed many hallmark properties for neuronal maturation, including robust electrical and synaptic activity. Using iNGNs expressing a variant of channelrhodopsin-2, called CatCh, we could control iNGN activity with blue light stimulation. In combination with optogenetic tools, iNGNs offer opportunities for studies that require precise spatial and temporal resolution. iNGNs developed spontaneous network activity, and these networks had excitatory glutamatergic synapses, which we characterized with single-cell synaptic recordings. AMPA glutamatergic receptor activity was especially dominant in postsynaptic recordings, whereas NMDA glutamatergic receptor activity was absent from postsynaptic recordings but present in extrasynaptic recordings. Our results on long-term cultures of iNGNs could help in future studies elucidating mechanisms of human synaptogenesis and neurotransmission, along with the ability to scale-up the size of the cultures.

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Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus

Cited by 89 publications

References 73 publications

β-Amyloid triggers aberrant over-scaling of homeostatic synaptic plasticity

β-Amyloid triggers aberrant over-scaling of homeostatic synaptic plasticity

Synaptic AMPA receptor composition in development, plasticity and disease

Functional Maturation of Human Stem Cell-Derived Neurons in Long-Term Cultures

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