An LRRTM4-HSPG Complex Mediates Excitatory Synapse Development on Dentate Gyrus Granule Cells

•The excitatory postsynaptic protein LRRTM4 binds heparan sulfate proteoglycans•Axonal HSPGs are necessary for LRRTM4 to induce presynaptic differentiation•LRRTM4 is selectively expressed in hippocampal dentate gyrus molecular layers•LRRTM4−/− mice show cell-specific deficits in excitatory synapse density and function

SummarySelective synapse development determines how complex neuronal networks in the brain are formed. Complexes of postsynaptic neuroligins and LRRTMs with presynaptic neurexins contribute widely to excitatory synapse development, and mutations in these gene families increase the risk of developing psychiatric disorders. We find that LRRTM4 has distinct presynaptic binding partners, heparan sulfate proteoglycans (HSPGs). HSPGs are required to mediate the synaptogenic activity of LRRTM4. LRRTM4 shows highly selective expression in the brain. Within the hippocampus, we detected LRRTM4 specifically at excitatory postsynaptic sites on dentate gyrus granule cells. LRRTM4−/− dentate gyrus granule cells, but not CA1 pyramidal cells, exhibit reductions in excitatory synapse density and function. Furthermore, LRRTM4−/− dentate gyrus granule cells show impaired activity-regulated AMPA receptor trafficking. These results identifying cell-type-specific functions and multiple presynaptic binding partners for different LRRTM family members reveal an unexpected complexity in the design and function of synapse-organizing proteins.