Glypicans as novel regulators of synaptic connectivity

The function of neural circuits depends on precise patterns of connectivity and the properties of synaptic transmission at specific synapses. The hippocampal mossy fiber (MF) synapse, which connects dentate gyrus granule cells with CA3 neurons, is a major information processing pathway and presents unique structural and functional properties. The molecular mechanisms governing MF synapse development and its specific structural-functional properties are largely unknown.Recently, we identified the presynaptic protein Glypican 4 (GPC4) as a novel synaptic organizing protein with a key role in excitatory synapse development. GPC4 is strongly enriched in the presynaptic compartment of MF synapses, but whether it is involved in MF synapse development or function is currently unknown.Using an in vivo knock down strategy we find that GPC4 controls the morphological maturation of MF presynaptic terminals. To dissect how GPC4 exerts this function, we performed a proteomic screen to identify novel GPC4 binding partners. We identified a largely uncharacterized, orphan G-protein coupled receptor, GPR158, as potential GPC4 interactor. Biochemical analysis demonstrates that GPC4 binds to GPR158 in a heparan sulfate-dependent manner, while localization studies indicate a specific GPR158 postsynaptic localization at the MF synapse. Further, we find that GPR158 stimulates presynaptic differentiation in cultured neurons in a GPC4-dependent manner. In GPR158 knockout mice, the characteristic presynaptic facilitation of MF synapses is strongly impaired. All together these data support the hypothesis that the GPC4-GPR158 interaction may act as MF synapse-specific interaction required for its development and function. We are currently dissecting the role of GPC4-GPR158 interaction in vivo during MF synapse development.

Publication year:2019