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@ARTICLE{Varbanov:257594,
author = {Varbanov, Hristo and Jia, Shaobo and Kochlamazashvili, Gaga
and Bhattacharya, Subhrajit and Buabeid, Manal Ali and El
Tabbal, Mohamed and Hayani, Hussam and Stoyanov, Stoyan and
Sun, Weilun and Thiesler, Hauke and Röckle, Iris and
Hildebrandt, Herbert and Senkov, Oleg and Suppiramaniam,
Vishnu and Gerardy-Schahn, Rita and Dityatev, Alexander},
title = {{R}escue of synaptic and cognitive functions in polysialic
acid-deficient mice and dementia models by short polysialic
acid fragments.},
journal = {Neurobiology of disease},
volume = {180},
issn = {0969-9961},
address = {[Amsterdam]},
publisher = {Elsevier},
reportid = {DZNE-2023-00470},
pages = {106079},
year = {2023},
abstract = {Dysregulated cortical expression of the neural cell
adhesion molecule (NCAM) and deficits of its associated
polysialic acid (polySia) have been found in Alzheimer's
disease and schizophrenia. However, the functional role of
polySia in cortical synaptic plasticity remains poorly
understood. Here, we show that acute enzymatic removal of
polySia in medial prefrontal cortex (mPFC) slices leads to
increased transmission mediated by the GluN1/GluN2B subtype
of N-methyl-d-aspartate receptors (NMDARs), increased
NMDAR-mediated extrasynaptic tonic currents, and impaired
long-term potentiation (LTP). The latter could be fully
rescued by pharmacological suppression of GluN1/GluN2B
receptors, or by application of short soluble polySia
fragments that inhibited opening of GluN1/GluN2B channels.
These treatments and augmentation of synaptic NMDARs with
the glycine transporter type 1 (GlyT1) inhibitor sarcosine
also restored LTP in mice deficient in polysialyltransferase
ST8SIA4. Furthermore, the impaired performance of
polySia-deficient mice and two models of Alzheimer's disease
in the mPFC-dependent cognitive tasks could be rescued by
intranasal administration of polySia fragments. Our data
demonstrate the essential role of polySia-NCAM in the
balancing of signaling through synaptic/extrasynaptic NMDARs
in mPFC and highlight the therapeutic potential of short
polySia fragments to restrain GluN1/GluN2B-mediated
signaling.},
keywords = {Mice / Animals / Alzheimer Disease: drug therapy / Sialic
Acids: metabolism / Cognition / Neural Cell Adhesion
Molecules: metabolism / Receptors, N-Methyl-D-Aspartate /
NCAM (Other) / NMDA receptor (Other) / Polysialic acid
(Other) / Prefrontal cortex (Other) / Synaptic plasticity
(Other) / polysialic acid (NLM Chemicals) / Sialic Acids
(NLM Chemicals) / Neural Cell Adhesion Molecules (NLM
Chemicals) / Receptors, N-Methyl-D-Aspartate (NLM
Chemicals)},
cin = {AG Dityatev},
ddc = {570},
cid = {I:(DE-2719)1310007},
pnm = {351 - Brain Function (POF4-351)},
pid = {G:(DE-HGF)POF4-351},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:36918046},
doi = {10.1016/j.nbd.2023.106079},
url = {https://pub.dzne.de/record/257594},
}