Astrocytic EphB3 receptors regulate D-serine-gated synaptic plasticity and memory

Langlais VC(1), Mountadem S(1), Benazzouz I(1), Amadio A(1), Matos M(1), Jourdes A(1), Cannich A(1), Julio-Kalajzic F(2), Belluomo I(1), Matias I(1), Maitre M(1), Lesté-Lasserre T(1), Marais S(3), Avignone E(1), Marsicano G(1), Bellocchio L(1), Oliet SHR(1), Panatier A(4).

Author information:
(1)Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000 Bordeaux,
France.
(2)Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000 Bordeaux,
France; Univ. Bordeaux, CNRS, INSERM, BIC, US4, UAR 3420, F-33000 Bordeaux,
France; Lead contact.
(3)Univ. Bordeaux, CNRS, INSERM, BIC, US4, UAR 3420, F-33000 Bordeaux, France.
(4)Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000 Bordeaux,
France; Lead contact. Electronic address: .

The activation of classical NMDA receptors (NMDARs) requires the binding of a
co-agonist in addition to glutamate. Whereas astrocytic-derived d-serine was
shown to play such a role at CA3-CA1 hippocampal synapses, the exact mechanism
by which neurons interact with neighboring astrocytes to regulate synaptic
d-serine availability remains to be fully elucidated. Considering the close
anatomical apposition of astrocytic and neuronal elements at synapses, the
aforementioned process is likely to involve cells adhesion molecules. One very
likely candidate could be the astrocytic EphB3 receptor and its neuronal
partner, ephrinB3. Here, we first showed in acute hippocampal slices from adult
mice that stimulation of EphB3 receptors with exogenous ephrinB3 increased
d-serine availability at CA3-CA1 synapses, resulting in an increased NMDAR
activity. Conversely, inhibiting endogenous EphB3 receptors caused an impairment
of both synaptic NMDAR activity and NMDAR-dependent long-term synaptic
potentiation (LTP), effects that could be rescued by exogenous d-serine. Most
interestingly, knocking down EphB3 receptor specifically in astrocytes yielded a
similar impairment in hippocampal plasticity and, most importantly, caused a
deficit in novel object recognition memory. Altogether, our data thus indicate
that EphB3 receptors in hippocampal astrocytes play a key role in regulating
synaptic NMDAR function, activity-dependent plasticity and memory.

Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Conflict of interest statement: Declaration of Competing Interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper. Declaration of Competing Interest The authors declare that they have not
known competing financial interests or personal relationships that could have
appeared to influence the work reported in this paper.

Auteurs Bordeaux Neurocampus