Journal Article

DZNE-2023-00470

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Rescue of synaptic and cognitive functions in polysialic acid-deficient mice and dementia models by short polysialic acid fragments.

Varbanov, H. (First author)DZNE* ; Jia, S.DZNE* ; Kochlamazashvili, G. ; Bhattacharya, S. ; Buabeid, M. A. ; El Tabbal, M.DZNE* ; Hayani, H.DZNE* ; Stoyanov, S.DZNE* ; Sun, W.DZNE* ; Thiesler, H. ; Röckle, I. ; Hildebrandt, H. ; Senkov, O.DZNE* ; Suppiramaniam, V. ; Gerardy-Schahn, R. ; Dityatev, A. (Last author)DZNE*

2023
Elsevier [Amsterdam]

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Please use a persistent id in citations: doi:10.1016/j.nbd.2023.106079

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.

Keyword(s): Mice (MeSH) ; Animals (MeSH) ; Alzheimer Disease: drug therapy (MeSH) ; Sialic Acids: metabolism (MeSH) ; Cognition (MeSH) ; Neural Cell Adhesion Molecules: metabolism (MeSH) ; Receptors, N-Methyl-D-Aspartate (MeSH) ; NCAM ; NMDA receptor ; Polysialic acid ; Prefrontal cortex ; Synaptic plasticity ; polysialic acid ; Sialic Acids ; Neural Cell Adhesion Molecules ; Receptors, N-Methyl-D-Aspartate

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Contributing Institute(s):

1. Molecular Neuroplasticity (AG Dityatev)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2023

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