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

Abstract

Selective 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.

PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

“…In recent years, SDCs and GPCs in particular have emerged as crucial regulators of cell migration and axon guidance in flies through binding to LAR (14,28). However, their roles in mammalian synapses have only begun to be elucidated (19,20,34). In the present study, we found that mammalian GPCs, but not SDCs, bind to mammalian LAR-RPTPs (Fig.…”

“…Based on the direct interaction of GPCs with LAR-RPTPs (this work), the direct interaction of GPCs with LRRTM4 (19,20) and the biochemical nature of GPCs as GPIanchored proteins, we hypothesized that LAR-RPTPs might be functional presynaptic receptors for LRRTM4. To directly address this hypothesis, we used previously characterized lentiviral shorthairpin interference RNAs (shRNAs) against PTPσ (sh-PTPσ) or LAR (sh-LAR) [ref.…”

APLP1 Is a Synaptic Cell Adhesion Molecule, Supporting Maintenance of Dendritic Spines and Basal Synaptic Transmission

“…Additionally, heterologous expression of SAMs in fibroblasts causes presynaptic differentiations in contacting axons of cocultivated neurons, which has been shown for Neuroligin, Neurexin, leucine-rich repeat transmembranes (LRRTMs), EphB-EphrinB, and Calsyntenin3 (Scheiffele et al, 2000;Biederer et al, 2002;Dean et al, 2003;Kayser et al, 2006;Dalva et al, 2007;Linhoff et al, 2009;Pettem et al, 2013). APP has also been demonstrated to induce so called hemisynapses in this coculture assay (Wang et al, 2009;Siddiqui and Craig, 2011;Stahl et al, 2014). In contrast, synaptogenic functions of APLP1 and APLP2 have not been reported so far.…”

“…Several features of APP indicate that it belongs to the family of SAMs (Siddiqui and Craig, 2011). It has been shown previously by several groups that APP is upregulated at different developmental stages in mouse brains, which are attributed to the period of synaptogenesis (Clarris et al, 1994;De Felipe et al, 1997;Hoe et al, 2009;Vella and Cappai, 2012).…”

“…Further, in addition to a function of sAPP as a neurotrophic factor (Weyer et al, 2011;Hick et al, 2015;Fol et al, 2016), several independent studies have suggested that APP has a synaptic adhesion molecule (SAM)-like function (Siddiqui and Craig, 2011). Criteria for SAMs include their synaptic localization, functions in cell-cell interaction, and indications for altered synapse formation upon the loss of function of these proteins.…”