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Featured ArticleResearch Articles, Neurobiology of Disease

Presenilin and APP Regulate Synaptic Kainate Receptors

Gaël Barthet, Ana Moreira-de-Sá, Pei Zhang, Séverine Deforges, Jorge Castanheira, Adam Gorlewicz and Christophe Mulle
Journal of Neuroscience 7 December 2022, 42 (49) 9253-9262; DOI: https://doi.org/10.1523/JNEUROSCI.0297-22.2022
Gaël Barthet
Université of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience (IINS), UMR 5297, F-33000 Bordeaux, France
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Ana Moreira-de-Sá
Université of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience (IINS), UMR 5297, F-33000 Bordeaux, France
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Pei Zhang
Université of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience (IINS), UMR 5297, F-33000 Bordeaux, France
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Séverine Deforges
Université of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience (IINS), UMR 5297, F-33000 Bordeaux, France
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Jorge Castanheira
Université of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience (IINS), UMR 5297, F-33000 Bordeaux, France
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Adam Gorlewicz
Université of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience (IINS), UMR 5297, F-33000 Bordeaux, France
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Christophe Mulle
Université of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience (IINS), UMR 5297, F-33000 Bordeaux, France
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Abstract

Kainate receptors (KARs) form a family of ionotropic glutamate receptors that regulate the activity of neuronal networks by both presynaptic and postsynaptic mechanisms. Their implication in pathologies is well documented for epilepsy. The higher prevalence of epileptic symptoms in Alzheimer's disease (AD) patients questions the role of KARs in AD. Here we investigated whether the synaptic expression and function of KARs was impaired in mouse models of AD. We addressed this question by immunostaining and electrophysiology at synapses between mossy fibers and CA3 pyramidal cells, in which KARs are abundant and play a prominent physiological role. We observed a decrease of the immunostaining for GluK2 in the stratum lucidum in CA3, and of the amplitude and decay time of synaptic currents mediated by GluK2-containing KARs in an amyloid mouse model (APP/PS1) of AD. Interestingly, a similar phenotype was observed in CA3 pyramidal cells in male and female mice with a genetic deletion of either presenilin or APP/APLP2 as well as in organotypic cultures treated with γ-secretase inhibitors. Finally, the GluK2 protein interacts with full-length and C-terminal fragments of APP. Overall, our data suggest that APP stabilizes KARs at synapses, possibly through a transsynaptic mechanism, and this interaction is under the control the γ-secretase proteolytic activity of presenilin.

SIGNIFICANCE STATEMENT Synaptic impairment correlates strongly with cognitive deficits in Alzheimer's disease (AD). In this context, many studies have addressed the dysregulation of AMPA and NMDA ionotropic glutamate receptors. Kainate receptors (KARs), which form the third family of iGluRs, represent an underestimated actor in the regulation of neuronal circuits and have not yet been examined in the context of AD. Here we provide evidence that synaptic KARs are markedly impaired in a mouse model of AD. Additional experiments indicate that the γ-secretase activity of presenilin acting on the amyloid precursor protein controls synaptic expression of KAR. This study clearly indicates that KARs should be taken into consideration whenever addressing synaptic dysfunction and related cognitive deficits in the context of AD.

  • Alzheimer's disease
  • APP
  • kainate receptors
  • presenilin
  • synapse

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The Journal of Neuroscience: 42 (49)
Journal of Neuroscience
Vol. 42, Issue 49
7 Dec 2022
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Presenilin and APP Regulate Synaptic Kainate Receptors
Gaël Barthet, Ana Moreira-de-Sá, Pei Zhang, Séverine Deforges, Jorge Castanheira, Adam Gorlewicz, Christophe Mulle
Journal of Neuroscience 7 December 2022, 42 (49) 9253-9262; DOI: 10.1523/JNEUROSCI.0297-22.2022

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Presenilin and APP Regulate Synaptic Kainate Receptors
Gaël Barthet, Ana Moreira-de-Sá, Pei Zhang, Séverine Deforges, Jorge Castanheira, Adam Gorlewicz, Christophe Mulle
Journal of Neuroscience 7 December 2022, 42 (49) 9253-9262; DOI: 10.1523/JNEUROSCI.0297-22.2022
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Keywords

  • Alzheimer's disease
  • APP
  • kainate receptors
  • presenilin
  • synapse

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