Neuron
Volume 100, Issue 1, 10 October 2018, Pages 201-215.e9
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Article
An Input-Specific Orphan Receptor GPR158-HSPG Interaction Organizes Hippocampal Mossy Fiber-CA3 Synapses

https://doi.org/10.1016/j.neuron.2018.08.038Get rights and content
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Highlights

  • The heparan sulfate proteoglycan (HSPG) GPC4 binds the orphan receptor GPR158

  • GPR158 is expressed in hippocampal CA3 neurons and restricted to mossy fiber inputs

  • Postsynaptic GPR158 induces presynaptic differentiation in a GPC4-dependent manner

  • GPR158 selectively organizes mossy fiber-CA3 synaptic architecture and function

Summary

Pyramidal neuron dendrites integrate synaptic input from multiple partners. Different inputs converging on the same dendrite have distinct structural and functional features, but the molecular mechanisms organizing input-specific properties are poorly understood. We identify the orphan receptor GPR158 as a binding partner for the heparan sulfate proteoglycan (HSPG) glypican 4 (GPC4). GPC4 is enriched on hippocampal granule cell axons (mossy fibers), whereas postsynaptic GPR158 is restricted to the proximal segment of CA3 apical dendrites receiving mossy fiber input. GPR158-induced presynaptic differentiation in contacting axons requires cell-surface GPC4 and the co-receptor LAR. Loss of GPR158 increases mossy fiber synapse density but disrupts bouton morphology, impairs ultrastructural organization of active zone and postsynaptic density, and reduces synaptic strength of this connection, while adjacent inputs on the same dendrite are unaffected. Our work identifies an input-specific HSPG-GPR158 interaction that selectively organizes synaptic architecture and function of developing mossy fiber-CA3 synapses in the hippocampus.

Keywords

synaptogenesis
synaptic specificity
heparan sulfate proteoglycan
orphan receptor
glutamatergic transmission
postsynaptic density
active zone
mossy fiber synapse
hippocampus
pyramidal neuron

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