Abstract
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. The molecular mechanisms by which pyramidal neurons organize the structural and functional properties of their synaptic inputs are poorly understood. Condomitti et al. identify an input-specific orphan receptor GPR158-HSPG interaction that selectively organizes mossy fiber inputs onto CA3 pyramidal neurons.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 201-215.e9 |
| Journal | Neuron |
| Volume | 100 |
| Issue number | 1 |
| DOIs | |
| State | Published - Oct 10 2018 |
Funding
We thank Patrik Verstreken and Dietmar Schmucker for critical reading of the manuscript and de Wit lab members for discussion and comments. We thank Heather Rice, Jeroen Vanderlinden, and Julie Nys for experimental help. We thank Katlijn Vints and Benjamin Pavie (VIB BioImaging Core, KU Leuven) for electron microscopy reagents and ImageJ scripts, respectively. We thank Jaewon Ko for generously providing LAR RPTP shRNA constructs and Thomas S\u00FCdhof for generously providing NRXN TKD plasmid. We thank Fahri K\u00FC\u00E7\u00FCkali and Kristel Sleegers (VIB-UAntwerp Center for Molecular Neurology) for analysis of GPR158 variants in neurodevelopmental disorders. Zeiss Elyra S.1 was acquired through a CLME grant from Minister Lieten to the VIB BioImaging Core. Leica SP8x confocal microscope provided by InfraMouse (KU Leuven-VIB) through a Hercules type 3 project (ZW09-03). This work was supported by an FWO PhD fellowship to A.S. ( 11Z3715N/17N ); an FWO postdoctoral fellowship to S.E.R. ( 12N3515N ); NIH grants MH105482 and DA026405 (K.A.M.); NIH grant R00DC013805 (J.N.S.); and ERC Starting Grant (# 311083 ), FWO Odysseus Grant, FWO Project grants G094016N and G0C4518N , Methusalem grant of KU Leuven/Flemish Government, and ERA-NET NEURON SynPathy 2015 to J.d.W.
Keywords
- active zone
- glutamatergic transmission
- heparan sulfate proteoglycan
- hippocampus
- mossy fiber synapse
- orphan receptor
- postsynaptic density
- pyramidal neuron
- synaptic specificity
- synaptogenesis
ASJC Scopus subject areas
- General Neuroscience