Abstract
Neural circuit assembly in the brain requires precise establishment of synaptic connections, but the mechanisms of synapse assembly remain incompletely understood. Latrophilins are postsynaptic adhesion-GPCRs that engage in trans-synaptic complexes with presynaptic teneurins and FLRTs. In mouse CA1-region neurons, Latrophilin-2 and Latrophilin-3 are essential for formation of entorhinal-cortex-derived and Schaffer-collateral-derived synapses, respectively. However, it is unknown whether latrophilins function as GPCRs in synapse formation. Here, we show that Latrophilin-2 and Latrophilin-3 exhibit constitutive GPCR activity that increases cAMP levels, which was blocked by a mutation interfering with G-protein and arrestin interactions of GPCRs. The same mutation impaired the ability of Latrophilin-2 and Latrophilin-3 to rescue the synapse-loss phenotype in Latrophilin-2 and Latrophilin-3 knockout neurons in vivo. Our results suggest that Latrophilin-2 and Latrophilin-3 require GPCR signaling in synapse formation, indicating that latrophilins promote synapse formation in the hippocampus by activating a classical GPCR-signaling pathway.
Highlights
Many proteins that shape synaptic functions have been identified, little is known about how synapses are generated
The Lphn2-T4L and Lphn3-T4L mutants contain an insertion of a T4 lysozyme (T4L) sequence into the 3rd intracellular loop of Lphn2 or Lphn3, which abolishes G-protein coupling and impairs arrestin signaling to these GPCRs (Rosenbaum et al, 2007; Cherezov et al, 2007; Thorsen et al, 2014)
Latrophilin-2 (Lphn2) and Latrophilin-3 (Lphn3) signal transduction mutants engage in teneurin- and FLRT-mediated intercellular interactions on the cell surface
Summary
Many proteins that shape synaptic functions have been identified, little is known about how synapses are generated. Few adhesion molecules appear to be required for the initial establishment of synapses Among these molecules are two families of adhesion-GPCRs, latrophilins and BAIs, that are essential for establishing synapses in all brain regions in which they have been tested Other potential mechanisms for the function of latrophilins in synapse formation are plausible, for example a pure adhesion mechanism To address this question, we here examined the GPCR signaling functions of latrophilins in cultured neurons and in vivo, testing this question using multiple independent approaches for two different latrophilins to ensure validity. Our data show that latrophilin-dependent synapse formation requires their GPCR-signaling activity that may have been adapted to synapses as a unique intercellular junction by use of a high degree of spatial compartmentalization
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