PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

Leukocyte common antigen-related receptor protein tyrosine phosphatases—comprising LAR, PTPδ, and PTPσ—are synaptic adhesion molecules that organize synapse development. Here, we identify glypican 4 (GPC-4) as a ligand for PTPσ. GPC-4 showed strong (nanomolar) affinity and heparan sulfate (HS)-dependent interaction with the Ig domains of PTPσ. PTPσ bound only to proteolytically cleaved GPC-4 and formed additional complex with leucine-rich repeat transmembrane protein 4 (LRRTM4) in rat brains. Moreover, single knockdown (KD) of PTPσ, but not LAR, in cultured neurons significantly reduced the synaptogenic activity of LRRTM4, a postsynaptic ligand of GPC-4, in heterologous synapse-formation assays. Finally, PTPσ KD dramatically decreased both the frequency and amplitude of excitatory synaptic transmission. This effect was reversed by wild-type PTPσ, but not by a HS-binding–defective PTPσ mutant. Our results collectively suggest that presynaptic PTPσ, together with GPC-4, acts in a HS-dependent manner to maintain excitatory synapse development and function. Significance This paper documents and systematically characterizes the molecular interactions of protein tyrosine phosphatase σ (PTPσ) with glypicans (GPCs). The identified interactions require heparan sulfate (HS), suggesting that GPCs are a major source of HS for PTPσ at excitatory synapses. Strikingly, we found that leucine-rich repeat transmembrane protein 4 (LRRTM4) induces presynaptic differentiation via the PTPσ/GPC interaction, suggesting that PTPσ may function as a coreceptor for GPCs in presynaptic neurons. More importantly, we found that HS-binding ability of PTPσ is critical for excitatory synaptic transmission. These results expand our previous understanding of how synaptic adhesion pathways regulate excitatory synapse development and shed light on GPCs/LRRTM4 trans -synaptic signaling. Moreover, to our knowledge, this is the first study to document the physiological significance of HS in the presynaptic function of mammalian neurons.