Rescue of synaptic and cognitive functions in polysialic acid-deficient mice and dementia models by short polysialic acid fragments

• Published in: Neurobiology of disease 2023-05, Vol.180, p.106079-106079, Article 106079
• Main Authors: Varbanov, Hristo, Jia, Shaobo, Kochlamazashvili, Gaga, Bhattacharya, Subhrajit, Buabeid, Manal Ali, El Tabbal, Mohamed, Hayani, Hussam, Stoyanov, Stoyan, Sun, Weilun, Thiesler, Hauke, Röckle, Iris, Hildebrandt, Herbert, Senkov, Oleg, Suppiramaniam, Vishnu, Gerardy-Schahn, Rita, Dityatev, Alexander
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Animals; Cognition; Mice; NCAM; Neural Cell Adhesion Molecules - metabolism; NMDA receptor; Polysialic acid; Prefrontal cortex; Receptors, N-Methyl-D-Aspartate; Sialic Acids - metabolism; Synaptic plasticity
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2023.106079

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. [Display omitted] •Polysialic acid depletion elevated signaling via extrasynaptic NMDA receptors in mPFC.•This resulted in impaired mPFC long-term potentiation and temporal order recognition.•These defects could be abrogated by targeting synaptic/extrasynaptic NMDA receptors.•The rescue was also achieved by delivery of polysialic acid fragments (NANA12).•NANA12 rescued synaptic/cognitive functions in models of amyloidosis and tauopathy.