Abstract
Heparan sulfate (HS) chains, covalently linked to heparan sulfate proteoglycans (HSPG), promote synaptic development and functions by connecting various synaptic adhesion proteins (AP). HS binding to AP could vary according to modifications of HS chains by different sulfotransferases. 3-O-sulfotransferases (Hs3sts) produce rare 3-O-sulfated HSs (3S-HSs), of poorly known functions in the nervous system. Here, we showed that a peptide known to block herpes simplex virus by interfering with 3S-HSs in vitro and in vivo (i.e. G2 peptide), specifically inhibited neural activity, reduced evoked glutamate release, and impaired synaptic assembly in hippocampal cell cultures. A role for 3S-HSs in promoting synaptic assembly and neural activity is consistent with the synaptic interactome of G2 peptide, and with the detection of Hs3sts and their products in synapses of cultured neurons and in synaptosomes prepared from developing brains. Our study suggests that 3S-HSs acting as receptors for herpesviruses might be important regulators of neuronal and synaptic development in vertebrates.
Highlights
Heparan sulfate (HS) chains, covalently linked to heparan sulfate proteoglycans (HSPG), promote synaptic development and functions by connecting various synaptic adhesion proteins (AP)
We first analyzed the expression of 3-O-sulfated HSs (3S-HSs) at synapse by using, the HS4C3 antibody that recognizes over sulfated HS and preferentially 3S-HSs31, Western-immunoblot (WB), and purified synaptosomal fractions enriched in presynaptic marker Vglut[1], and in postsynaptic marker PSD-95 (Fig. S1, Supplementary file)
G2-F, a fluorescent form of G2 peptide recognizing glycoprotein D (gD)-type 3S-HSs26 and which binds to heparan sulfates onto cell membrane in vitro[30] produces, as HS4C3 Ab, a punctiform labelling at the surface of hippocampal cell neurites (Fig. 1C)
Summary
Heparan sulfate (HS) chains, covalently linked to heparan sulfate proteoglycans (HSPG), promote synaptic development and functions by connecting various synaptic adhesion proteins (AP). While several Hs3Sts, including Hs3st[2] and Hs3st[4], are preferentially expressed at the time of synaptic formation in the mouse brain[19], it is not known whether 3S-HSs are present at the synapse and/or if they impact neural functions and signaling in mice Establishing this is fundamental because HSs and 3S-HSs have been associated to pathological processes impacting synapses, including HSV-1 infections[20], and psychiatric diseases such as Scientific Reports | (2020) 10:19114. Our approach allowed to characterize different proteins of the gD-type 3S-HS signaling pathway(s) linked to the life cycle of HSV-1 and/or involved in synaptic organization The importance of these pathways, never described at this level for a modification of HS, is outlined by specific inhibitory effects of anti-3S-HSs peptides on developing neuronal cells
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