Sustained postsynaptic kainate receptor activation downregulates AMPA receptor surface expression and induces hippocampal LTD

AbstractHere we report that sustained activation of GluK2 subunit-containing kainate receptors leads to AMPA receptor endocytosis and a novel form of long-term depression (KAR-LTDAMPAR) in hippocampal neurons. The KAR-evoked loss of surface AMPA receptors requires KAR channel activity and is occluded by the blockade of PKC or PKA. Moreover, in acute hippocampal slices, kainate invoked LTD of AMPA EPSCs. These data, together with our previously reported KAR-LTPAMPAR, demonstrate that KARs bidirectionally regulate synaptic AMPARs and synaptic plasticity.

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Analysis of Glutamate Receptor Surface Expression in Acute Hippocampal Slices

Science Signaling ◽

10.1126/stke.2002.137.pl8 ◽

2002 ◽

Vol 2002 (137) ◽

pp. pl8-pl8 ◽

Cited By ~ 9

Author(s):

D. R. Grosshans ◽

D. A. Clayton ◽

S. J. Coultrap ◽

M. D. Browning

Keyword(s):

Glutamate Receptor ◽

Hippocampal Slices ◽

Surface Expression ◽

Receptor Surface Expression ◽

Acute Hippocampal Slices

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CPEB2 Activates GRASP1 mRNA Translation and Promotes AMPA Receptor Surface Expression, Long-Term Potentiation, and Memory

Cell Reports ◽

10.1016/j.celrep.2017.10.073 ◽

2017 ◽

Vol 21 (7) ◽

pp. 1783-1794 ◽

Cited By ~ 11

Author(s):

Wen-Hsin Lu ◽

Nai-Hsing Yeh ◽

Yi-Shuian Huang

Keyword(s):

Ampa Receptor ◽

Mrna Translation ◽

Long Term Potentiation ◽

Surface Expression ◽

Term Potentiation ◽

Receptor Surface Expression

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REGULATION OF AMPA RECEPTOR SURFACE EXPRESSION BY A NSF-DEPENDENT MECHANISM IN HIPPOCAMPAL NEURONS IN CULTURE

Biochemical Society Transactions ◽

10.1042/bst027a117b ◽

1999 ◽

Vol 27 (3) ◽

pp. A117-A117

Author(s):

J. Noel ◽

G. Scott Ralph ◽

L. Pickard ◽

E. Molnar ◽

J. B. Uney ◽

...

Keyword(s):

Ampa Receptor ◽

Hippocampal Neurons ◽

Surface Expression ◽

Receptor Surface Expression ◽

Dependent Mechanism

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Combined β-adrenergic and corticosteroid receptor activation regulates AMPA receptor function in hippocampal neurons

Journal of Psychopharmacology ◽

10.1177/0269881111424930 ◽

2011 ◽

Vol 26 (4) ◽

pp. 516-524 ◽

Cited By ~ 16

Author(s):

Ming Zhou ◽

Casper C Hoogenraad ◽

Marian Joëls ◽

Harm J Krugers

Keyword(s):

Adrenergic Receptors ◽

Hippocampal Neurons ◽

Hippocampal Slices ◽

Primary Cultures ◽

Surface Expression ◽

Receptor Activation ◽

Behavioural Adaptation ◽

Corticosteroid Receptor ◽

Β Adrenergic Receptors ◽

Enhanced Surface

Shortly after stress, limbic neurons are exposed to high levels of noradrenaline and corticosterone. These hormones are necessary for optimal behavioural adaptation. Behavioural effects critically depend on noradrenaline acting via β-adrenergic receptors, but these effects are strongly modulated by corticosterone, indicating putative interactions between the two hormones. Since both noradrenaline and corticosterone are known to quickly affect properties of AMPA-type glutamate receptors (AMPAR), we here examined – in hippocampal neurons – three parameters which give insight in the functionality of AMPARs: phosphorylation, surface expression and spontaneous synaptic transmission. In homogenates of adult hippocampal slices, application of corticosterone (30 nM for 15 min) by itself did not affect phosphorylation of the AMPAR GluA1 subunit at S845 or S831. Co-application of the β-adrenergic receptor agonist isoproterenol (10 µM) largely increased S845 (but not S831) phosphorylation. Corticosterone also did not change GluA1 and GluA2 surface expression in hippocampal primary cultures. However, combined administration of corticosterone and 1 µM isoproterenol – which by itself was ineffective – enhanced surface expression. Interestingly, 10 µM isoproterenol alone enhanced GluA1 surface expression, but this was decreased by corticosterone. Finally, in hippocampal primary cultures, the inter-event interval of miniature excitatory postsynaptic currents (mEPSCs) was decreased by the combination of 1 µM isoproterenol and corticosterone (which were ineffective by themselves) while the same combination did not affect the amplitude. We conclude that AMPAR phosphorylation, surface expression and mEPSC inter-event interval respond most strongly to a combination of corticosterone and β-adrenergic receptors. These combined hormonal effects on glutamate transmission might contribute to their memory-enhancing effects.

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GSK-3β regulates the synaptic expression of NMDA receptors via phosphorylation of phosphatidylinositol 4 kinase type IIα

10.1101/841676 ◽

2019 ◽

Author(s):

Mascia Amici ◽

Yeseul Lee ◽

Robert J.P. Pope ◽

Graham L. Collingridge

Keyword(s):

Nmda Receptors ◽

Ampa Receptors ◽

Hippocampal Slices ◽

Surface Expression ◽

Normal Functions ◽

Major Interest ◽

The Central Nervous System ◽

Gsk 3Β ◽

Phosphatidylinositol 4

ABSTRACTUnderstanding the normal functions of GSK-3β in the central nervous system is of major interest because deregulation of this kinase is strongly implicated in a variety of serious brain conditions, such as Alzheimer disease, bipolar disorder and schizophrenia. GSK-3β plays a role in the induction of NMDA receptor-dependent long-term depression (LTD) and several substrates for GSK-3β have been identified in this form of synaptic plasticity, including KLC-2, PSD-95 and tau. Stabilization of NMDA receptors at synapses has also been shown to involve GSK-3β, but the substrates involved are currently unknown. Recent work has identified phosphatidylinositol 4 kinase type IIα (PI4KIIα) as a neuronal GSK-3β substrate that can potentially regulate the surface expression of AMPA receptors. In the present study, we investigated the synaptic role of PI4KIIα in organotypic rat hippocampal slices. We found that knockdown of PI4KIIα had no effect on synaptic AMPA receptors but substantially inhibited synaptic NMDA receptors. Furthermore, the ability of the selective GSK-3 inhibitor, CT99021, to inhibit synaptic NMDA receptors was occluded in shRNA-PI4KIIα transfected neurons. The effects of knocking down PI4KIIα knockdown were fully rescued by a shRNA-resistant wild type construct but could not be rescued by a mutant construct that was unable to be phosphorylated by GSK-3β. The data suggest that GSK-3β phosphorylates PI4KIIα to stabilize the expression of synaptic NMDA receptors.

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MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1900338116 ◽

2019 ◽

Vol 116 (12) ◽

pp. 5727-5736 ◽

Cited By ~ 8

Author(s):

Mariline M. Silva ◽

Beatriz Rodrigues ◽

Joana Fernandes ◽

Sandra D. Santos ◽

Laura Carreto ◽

...

Keyword(s):

Ampa Receptor ◽

Ampa Receptors ◽

Hippocampal Neurons ◽

Surface Expression ◽

Receptor Expression ◽

Synaptic Activity ◽

Synaptic Scaling ◽

Posttranscriptional Control ◽

Direct Target ◽

Activity Dependent

Homeostatic synaptic scaling is a negative feedback response to fluctuations in synaptic strength induced by developmental or learning-related processes, which maintains neuronal activity stable. Although several components of the synaptic scaling apparatus have been characterized, the intrinsic regulatory mechanisms promoting scaling remain largely unknown. MicroRNAs may contribute to posttranscriptional control of mRNAs implicated in different stages of synaptic scaling, but their role in these mechanisms is still undervalued. Here, we report that chronic blockade of glutamate receptors of the AMPA and NMDA types in hippocampal neurons in culture induces changes in the neuronal mRNA and miRNA transcriptomes, leading to synaptic upscaling. Specifically, we show that synaptic activity blockade persistently down-regulates miR-186-5p. Moreover, we describe a conserved miR-186-5p-binding site within the 3′UTR of the mRNA encoding the AMPA receptor GluA2 subunit, and demonstrate that GluA2 is a direct target of miR-186-5p. Overexpression of miR-186 decreased GluA2 surface levels, increased synaptic expression of GluA2-lacking AMPA receptors, and blocked synaptic scaling, whereas inhibition of miR-186-5p increased GluA2 surface levels and the amplitude and frequency of AMPA receptor-mediated currents, and mimicked excitatory synaptic scaling induced by synaptic inactivity. Our findings elucidate an activity-dependent miRNA-mediated mechanism for regulation of AMPA receptor expression.

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Homeostatic plasticity induced by brief activity deprivation enhances long-term potentiation in the mature rat hippocampus

Journal of Neurophysiology ◽

10.1152/jn.00058.2014 ◽

2014 ◽

Vol 112 (11) ◽

pp. 3012-3022 ◽

Cited By ~ 16

Author(s):

A. Félix-Oliveira ◽

R. B. Dias ◽

M. Colino-Oliveira ◽

D. M. Rombo ◽

A. M. Sebastião

Keyword(s):

Synaptic Transmission ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Receptor Activation ◽

Relative Strength ◽

Homeostatic Plasticity ◽

Hebbian Plasticity ◽

Term Potentiation ◽

Acute Hippocampal Slices

Different forms of plasticity occur concomitantly in the nervous system. Whereas homeostatic plasticity monitors and maintains neuronal activity within a functional range, Hebbian changes such as long-term potentiation (LTP) modify the relative strength of specific synapses after discrete changes in activity and are thought to provide the cellular basis for learning and memory. Here, we assessed whether homeostatic plasticity could influence subsequent LTP in acute hippocampal slices that had been briefly deprived of activity by blocking action potential generation and N-methyl-d-aspartate (NMDA) receptor activation for 3 h. Activity deprivation enhanced the frequency and the amplitude of spontaneous miniature excitatory postsynaptic currents and enhanced basal synaptic transmission in the absence of significant changes in intrinsic excitability. Changes in the threshold for Hebbian plasticity were evaluated by inducing LTP with stimulation protocols of increasing strength. We found that activity-deprived slices consistently showed higher LTP magnitude compared with control conditions even when using subthreshold theta-burst stimulation. Enhanced LTP in activity-deprived slices was also observed when picrotoxin was used to prevent the modulation of GABAergic transmission. Finally, we observed that consecutive LTP inductions attained a higher magnitude of facilitation in activity-deprived slices, suggesting that the homeostatic plasticity mechanisms triggered by a brief period of neuronal silencing can both lower the threshold and raise the ceiling for Hebbian modifications. We conclude that even brief periods of altered activity are able to shape subsequent synaptic transmission and Hebbian plasticity in fully developed hippocampal circuits.

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SUMOylation Is Required for Glycine-Induced Increases in AMPA Receptor Surface Expression (ChemLTP) in Hippocampal Neurons

PLoS ONE ◽

10.1371/journal.pone.0052345 ◽

2013 ◽

Vol 8 (1) ◽

pp. e52345 ◽

Cited By ~ 38

Author(s):

Nadia Jaafari ◽

Filip A. Konopacki ◽

Thomas F. Owen ◽

Sriharsha Kantamneni ◽

Philip Rubin ◽

...

Keyword(s):

Ampa Receptor ◽

Hippocampal Neurons ◽

Surface Expression ◽

Receptor Surface Expression

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A selective LTP of NMDA receptor-mediated currents induced by anoxia in CA1 hippocampal neurons

Journal of Neurophysiology ◽

10.1152/jn.1993.70.5.2045 ◽

1993 ◽

Vol 70 (5) ◽

pp. 2045-2055 ◽

Cited By ~ 98

Author(s):

V. Crepel ◽

C. Hammond ◽

P. Chinestra ◽

D. Diabira ◽

Y. Ben-Ari

Keyword(s):

Nmda Receptor ◽

Ampa Receptor ◽

Ampa Receptors ◽

Hippocampal Neurons ◽

Long Term Potentiation ◽

Peak Amplitude ◽

Excitatory Postsynaptic Potential ◽

Physiological Concentration ◽

Term Potentiation

1. The possibility of long-lasting modifications of glutamatergic responses after anoxic-aglycemic (AA) episodes was investigated in CA1 hippocampal neurons of adult slices. Bicuculline (10 microM) was continuously bath applied to block GABAA receptor-mediated currents. AA episodes were induced by brief (1.30-3 min) perfusions with a glucose free artificial-cerebro-spinal-fluid (ACSF) saturated with 95% N2-5% CO2. 2. In presence of (0.6 mM) Mg2+ and a low concentration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 1 microM), the Schaffer collateral field EPSPs consisted of an early AMPA receptor-mediated component and a late N-methyl-D-aspartate (NMDA) receptor-mediated component. The former was blocked by (10 microM) CNQX and the latter by (50) microM D-2-amino-5-phosphonovalerate (D-APV). The AA episode induced a selective long-term potentiation (LTP) of the NMDA receptor-mediated component [+70 +/- 13% (mean +/- SE), P < or = 0.008, n = 9] without affecting significantly the AMPA receptor-mediated component (+2 +/- 4, P < or = 0.86 n = 9). This selective LTP is due to an enhanced efficacy of synaptic transmission and will be referred to as anoxic LTP. 3. In slices perfused with an ACSF containing a physiological concentration of (1.3 mM) Mg2+ and no CNQX, the intracellularly recorded excitatory postsynaptic potential (EPSP) was mixed (AMPA/NMDA) at -65 mV and exclusively mediated by AMPA receptors at -100 mV. At -65 mV, the AA episode induced a persistent potentiation of the EPSP (peak amplitude potentiated by 43 +/- 6%, P < or = 0.008, n = 9, 1 h after return to control ACSF). This potentiated component of the EPSP was fully sensitive to (50 microM) D-APV. The CNQX-sensitive AMPA receptor-mediated component was not affected by the AA episode (-5.7 +/- 6%, P < or = 0.123, n = 9). Furthermore, at -100 mV a large APV-sensitive component appeared after the AA episode (+58 +/- 18% of the peak amplitude, P < or = 0.018, n = 9). Therefore, the AA episode induced a selective LTP of the NMDA receptor-mediated component of the EPSP. 4. A robust LTP (+50.0 +/- 7.5%, P < or = 0.008, n = 12) of the NMDA receptor-mediated intracellular EPSP was also observed when AMPA receptors were fully and continuously blocked by (15 microM) CNQX.(ABSTRACT TRUNCATED AT 400 WORDS)

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