PTP sigma Drives Excitatory Presynaptic Assembly via Various Extracellular and Intracellular Mechanisms

Leukocyte common antigen-receptor protein tyrosine phosphatases (LAR-RPTPs) are hub proteins that organize excitatory and inhibitory synapse development through binding to various extracellular ligands. Here, we report that knockdown (KD) of the LAR-RPTP family member PTP sigma reduced excitatory synapse number and transmission in cultured rat hippocampal neurons, whereas KD of PTP delta produced comparable decreases at inhibitory synapses, in both cases without altering expression levels of interacting proteins. An extensive series of rescue experiments revealed that extracellular interactions of PTP sigma with Slitrks are important for excitatory synapse development. These experiments further showed that the intracellular D2 domain of PTP sigma is required for induction of heterologous synapse formation by Slitrk1 or TrkC, suggesting that interaction of LAR-RPTPs with distinct intracellular presynaptic proteins, drives presynaptic machinery assembly. Consistent with this, double-KD of liprin-alpha 2 and -alpha 3 or KD of PTP sigma substrates (N-cadherin and p250RhoGAP) in neurons inhibited Slitrk6-induced, PTP sigma-mediated heterologous synapse formation activity. We propose a synaptogenesis model in presynaptic neurons involving LAR-RPTP-organized retrograde signaling cascades, in which both extracellular and intracellular mechanisms are critical in orchestrating distinct synapse types.