An Input-Specific Orphan Receptor GPR158-HSPG Interaction Organizes Hippocampal Mossy Fiber-CA3 Synapses

Neuron. 2018 Oct 10;100(1):201-215.e9. doi: 10.1016/j.neuron.2018.08.038. Epub 2018 Oct 2.


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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA3 Region, Hippocampal / embryology
  • CA3 Region, Hippocampal / metabolism*
  • HEK293 Cells
  • Heparan Sulfate Proteoglycans / metabolism*
  • Humans
  • Mice
  • Mossy Fibers, Hippocampal / embryology
  • Mossy Fibers, Hippocampal / metabolism*
  • Neurogenesis / physiology
  • Pyramidal Cells / metabolism
  • Rats
  • Rats, Long-Evans
  • Receptors, G-Protein-Coupled / metabolism*
  • Synapses / metabolism*
  • Synaptic Transmission / physiology


  • Heparan Sulfate Proteoglycans
  • Receptors, G-Protein-Coupled