Excitatory synapse formation by trans-synaptic adhesions between NGL-3 and receptor protein tyrosine phosphatases LAR, PTPdelta, and PTPsigma

Abstract

Synaptic cell adhesion molecules have been involved in the control of various aspects of synaptic development. Some known synaptic adhesion molecules bind trans-synaptically and heterophilically, and regulate the synapse formation in diverse synapses. I studied that NGL-3, a PSD-95-interacting postsynaptic adhesion molecule, and LAR, a receptor protein tyrosine phosphatase, expressed in heterologous cells induce pre- and postsynaptic differentiation in contacting axons and dendrites of cocultured rat hippocampal neurons, respectively. Neuronal over expression of NGL-3 increases presynaptic contacts on dendrites of transfected neurons. Knockdown of NGL-3 reduces excitatory synapses. Competitive inhibition by soluble LAR reduces NGL-3-induced presynaptic differentiation. The first two FNIII domains of LAR are molecular determinant for interacting with NGL-3, and the other LAR family members, PTP$\delta$ and PTP$\sigma$, also can bind to NGL-3 via first two FNIII domains. These two interactions promote synapse formation in a different manner; the PTP$\sigma$-NGL-3 interaction promotes synapse formation in a bidirectional manner, whereas the PTP$\delta$-NGL-3 interaction instructs only presynaptic differentiation in a unidirectional manner. mRNAs encoding LAR family proteins display overlapping and differential expression patterns in various brain regions. These results suggest that trans-synaptic adhesion between NGL-3 and the three LAR family proteins regulates excitatory synapse formation in shared and distinct neural circuits.