The correct connectivity of the DG-CA3 circuits involved in declarative memory processes depends on Vangl2-dependent planar cell polarity signaling
Progress in Neurobiology. 2025-03-01; 246: 102728
DOI: 10.1016/j.pneurobio.2025.102728
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https://www.bordeaux-neurocampus.fr/11793
Depret N(1), Gleizes M(1), Moreau MM(1), Poirault-Chassac S(1), Quiedeville
A(1), Carvalho SDS(1), Venugopal V(1), Abed ASA(1), Ezan J(1), Barthet G(2),
Mulle C(2), Desmedt A(1), Marighetto A(1), Racca C(3), Montcouquiol M(1), Sans
N(4).
Author information:
(1)Univ. Bordeaux, Inserm, Neurocentre Magendie, U1215, Bordeaux F-33000,
France.
(2)Univ. Bordeaux, CNRS, IINS, UMR 5297, Bordeaux F-33000, France.
(3)Biosciences Institute, The Medical School, Newcastle University, Newcastle
upon Tyne, United Kingdom.
(4)Univ. Bordeaux, Inserm, Neurocentre Magendie, U1215, Bordeaux F-33000,
France. Electronic address: .
In the hippocampus, dentate gyrus granule cells connect to CA3 pyramidal cells
via their axons, the mossy fibers (Mf). The synaptic terminals of Mfs (Mf
boutons, MfBs) form large and complex synapses with thorny excrescences (TE) on
the proximal dendrites of CA3 pyramidal cells (PCs). MfB/TE synapses have
distinctive « detonator » properties due to low initial release probability and
large presynaptic facilitation. The molecular mechanisms shaping the
morpho-functional properties of MfB/TE synapses are still poorly understood,
though alterations in their morphology are associated with Down syndrome,
intellectual disabilities, and Alzheimer’s disease. Here, we identify the core
PCP gene Vangl2 as essential to the morphogenesis and function of MfB/TE
synapses. Vangl2 colocalises with the presynaptic heparan sulfate proteoglycan
glypican 4 (GPC4) to stabilise the postsynaptic orphan receptor GPR158.
Embryonic loss of Vangl2 disrupts the morphology of MfBs and TEs, impairs
ultrastructural and molecular organisation, resulting in defective synaptic
transmission and plasticity. In adult, the early loss of Vangl2 results in a
number of hippocampus-dependent memory deficits including characteristic
flexibility of declarative memory, organisation and retention of working /
everyday-like memory. These deficits also lead to abnormal generalisation of
memories to salient cues and diminished ability to form detailed contextual
memories. Together, these results establish Vangl2 as a key regulator of DG-CA3
connectivity and functions.
Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.pneurobio.2025.102728
PMID: 39956311 [Indexed for MEDLINE]
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.