Sensory Experience Differentially Modulates the mRNA Expression of the Polysialyltransferases ST8SiaII and ST8SiaIV in Postnatal Mouse Visual Cortex

Polysialic acid (PSA) is a unique carbohydrate composed of a linear homopolymer of α-2,8 linked sialic acid, and is mainly attached to the fifth immunoglobulin-like domain of the neural cell adhesion molecule (NCAM) in vertebrate neural system. In the brain, PSA is exclusively synthesized by the two polysialyltransferases ST8SiaII (also known as STX) and ST8SiaIV (also known as PST). By modulating adhesive property of NCAM, PSA plays a critical role in several neural development processes such as cell migration, neurite outgrowth, axon pathfinding, synaptogenesis and activity-dependent plasticity. The expression of PSA is temporally and spatially regulated during neural development and a tight regulation of PSA expression is essential to its biological function. In mouse visual cortex, PSA is downregulated following eye opening and its decrease allows the maturation of GABAergic synapses and the opening of the critical period for ocular dominance plasticity. Relatively little is known about how PSA levels are regulated by sensory experience and neuronal activity. Here, we demonstrate that while both ST8SiaII and ST8SiaIV mRNA levels decrease around the time of eye opening in mouse visual cortex, only ST8SiaII mRNA level reduction is regulated by sensory experience. Using an organotypic culture system from mouse visual cortex, we further show that ST8SiaII gene expression is regulated by spiking activity and NMDA-mediated excitation. Further, we show that both ST8SiaII and ST8SiaIV mRNA levels are positively regulated by PKC-mediated signaling. Therefore, sensory experience-dependent ST8SiaII gene expression regulates PSA levels in postnatal visual cortex, thus acting as molecular link between visual activity and PSA expression

Brain development needs sugar: The role of polysialic acid in controlling NCAM functions

Polysialic acid (polySia) is a major regulator of cell-cell interactions in the developing nervous system and a key factor in maintaining neural plasticity. As a polyanionic molecule with high water binding capacity, polySia increases the intercellular space and creates conditions that are permissive for cellular plasticity. While the prevailing model highlights polySia as a non-specific regulator of cell-cell contacts, this review concentrates on recent studies in knockout mice indicating that a crucial function of polySia resides in controlling interactions mediated by its predominant protein carrier, the neural cell adhesion molecule NCAM

Imbalance of neural cell adhesion molecule and polysialyltransferase alleles causes defective brain connectivity

The neural cell adhesion molecule (NCAM) and its post-translational modification polysialic acid (polySia) are broadly implicated in neural development. Mice lacking the polysialyltransferases ST8SiaII and ST8SiaIV are devoid of polySia, and show severe malformation of major brain axon tracts. Here, we demonstrate how allelic variation of three interacting gene products (NCAM, ST8SiaII and ST8SiaIV) translates into various degrees of anterior commissure, corpus callosum and internal capsule hypoplasia. Loss of ST8SiaII alone caused mild, but distinct defects and the severity of the pathological phenotype found in mice lacking both polysialyltransferases could be stepwise attenuated by reducing NCAM expression. Analysis of mice with overall nine selected combinations of mutant NCAM and polysialyltransferase alleles revealed that the extent of the fibre tract deficiencies was not linked to the total amount of polySia or NCAM, but correlated strictly with the level of NCAM erroneously devoid of polySia during brain development. The defects implemented by the gain of polySia-free NCAM were reminiscent to abnormalities found in patients with schizophrenia. Since variations in NCAM1 and ST8SIA2 have been implicated in schizophrenia, these findings provide a mechanism how genetic interference with the complex coordination of NCAM polysialylation may lead to a neurodevelopmental predisposition to schizophrenia

Synaptic cell adhesion molecule SynCAM 1 is a target for polysialylation in postnatal mouse brain

Among the large set of cell surface glycan structures, the carbohydrate polymer polysialic acid (polySia) plays an important role in vertebrate brain development and synaptic plasticity. The main carrier of polySia in the nervous system is the neural cell adhesion molecule NCAM. As polySia with chain lengths of more than 40 sialic acid residues was still observed in brain of newborn Ncam−/− mice, we performed a glycoproteomics approach to identify the underlying protein scaffolds. Affinity purification of polysialylated molecules from Ncam−/− brain followed by peptide mass fingerprinting led to the identification of the synaptic cell adhesion molecule SynCAM 1 as a so far unknown polySia carrier. SynCAM 1 belongs to the Ig superfamily and is a powerful inducer of synapse formation. Importantly, the appearance of polysialylated SynCAM 1 was not restricted to the Ncam−/− background but was found to the same extent in perinatal brain of WT mice. PolySia was located on N-glycans of the first Ig domain, which is known to be involved in homo- and heterophilic SynCAM 1 interactions. Both polysialyltransferases, ST8SiaII and ST8SiaIV, were able to polysialylate SynCAM 1 in vitro, and polysialylation of SynCAM 1 completely abolished homophilic binding. Analysis of serial sections of perinatal Ncam−/− brain revealed that polySia-SynCAM 1 is expressed exclusively by NG2 cells, a multifunctional glia population that can receive glutamatergic input via unique neuron-NG2 cell synapses. Our findings sug-gest that polySia may act as a dynamic modulator of SynCAM 1 functions during integration of NG2 cells into neural networks