Presenilin and APP regulate synaptic kainate receptors.

Gael Barthet, Ana Moreira- de-Sá, Pei Zhang, Séverine Deforges, Jorge Castanheira, Adam Gorlewicz, Christophe Mulle
J. Neurosci.. 2022-10-26; : JN-RM-0297-22
DOI: 10.1523/jneurosci.0297-22.2022

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Barthet G(1)(2), de-Sá AM(1)(2), Zhang P(1)(2), Deforges S(1)(2), Castanheira J, Gorlewicz A, Mulle C(3)(2).

Author information:
(1)Interdisciplinary Institute for Neuroscience, CNRS UMR 5297.
(2)University of Bordeaux, F-33000 Bordeaux, France.
(3)Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 .

Kainate receptors (KARs) form a family of ionotropic glutamate receptors which
regulate the activity of neuronal networks by both pre- and post-synaptic
mechanisms. Their implication in pathologies is well documented for epilepsy.
The higher prevalence of epileptic symptoms in Alzheimer 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 (male and
female APP/PS1 mice) 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 trans-synaptic 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
(iGluRs). 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. Further experiments
indicate that the gamma-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.

Copyright © 2022 the authors.

Conflict of interest statement: “The authors declare no competing financial interests.”

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