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

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/LRRTM4trans -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.