APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors

被引：4

作者：

Dunot, Jade ^{[1
,2
]}

Moreno, Sebastien ^{[1
]}

Gandin, Carine ^{[1
]}

Pousinha, Paula A. ^{[1
]}

Amici, Mascia ^{[3
]}

Dupuis, Julien ^{[4
]}

Anisimova, Margarita ^{[5
]}

Winschel, Alex ^{[6
]}

Uriot, Magalie ^{[4
]}

Petshow, Samuel J. ^{[5
]}

Mensch, Maria ^{[1
]}

Bethus, Ingrid ^{[1
]}

Giudici, Camilla ^{[7
]}

Hampel, Heike ^{[8
]}

Wefers, Benedikt ^{[7
,9
]}

Wurst, Wolfgang ^{[2
,7
,9
]}

Naumann, Ronald ^{[1
,10
]}

Ashby, Michael C. ^{[3
]}

Laube, Bodo ^{[6
]}

Zito, Karen ^{[5
]}

Mellor, Jack R. ^{[3
]}

Groc, Laurent ^{[4
]}

Willem, Michael ^{[8
]}

Marie, Helene ^{[1
]}

机构：

[1] Univ Cote Azur, CNRS, INSERM, Inst Pharmacol Mol & Cellulaire, F-06560 Valbonne, France

[2] Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany

[3] Univ Bristol, Ctr Synapt Plast, Sch Physiol Pharmacol & Neurosci, Bristol BS8 1TD, England

[4] Univ Bordeaux, CNRS, Interdisciplinary Inst Neurosci, F-33076 Bordeaux, France

[5] Univ Calif Davis, Ctr Neurosci, Davis, CA 95618 USA

[6] Tech Univ Darmstadt, Dept Biol Neurophysiol & Neurosensory Syst, D-64287 Darmstadt, Germany

[7] German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany

[8] Ludwig Maximilians Univ Munchen, Fac Med, Biomed Ctr BMC, Div Metab Biochem, D-81377 Munich, Germany

[9] Helmholtz Zentrum Munchen, Inst Dev Genet, D-85764 Neuherberg, Germany

[10] Max Planck Inst Mol Cell Biol & Genet, D-01307 Dresden, Germany

来源：

NEURON | 2024年 / 112卷 / 16期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金; 欧洲研究理事会;

关键词：

SYNAPTIC PLASTICITY; ALLOSTERIC MODULATION; SILENT SYNAPSES; VARIANTS; DISEASE;

D O I：

10.1016/j.neuron.2024.05.027

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

NMDA receptors (NMDARs) are ionotropic receptors crucial for brain information processing. Yet, evidence also supports an ion-flux-independent signaling mode mediating synaptic long-term depression (LTD) and spine shrinkage. Here, we identify AETA (Ah), an amyloid-b precursor protein (APP) cleavage product, as an NMDAR modulator with the unique dual regulatory capacity to impact both signaling modes. AETA inhibits ionotropic NMDAR activity by competing with the co-agonist and induces an intracellular conformational modification of GluN1 subunits. This favors non-ionotropic NMDAR signaling leading to enhanced LTD and favors spine shrinkage. Endogenously, AETA production is increased by in vivo chemogenetically induced neuronal activity. Genetic deletion of AETA production alters NMDAR transmission and prevents LTD, phenotypes rescued by acute exogenous AETA application. This genetic deletion also impairs contextual fear memory. Our findings demonstrate AETA-dependent NMDAR activation (ADNA), characterizing AETA as a unique type of endogenous NMDAR modulator that exerts bidirectional control over NMDAR signaling and associated information processing.

引用

页码：2708 / 2720.e9

页数：23

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