, 2010) and LAR family receptor protein tyrosine phosphatase (LAR-PTP)-binding postsynaptic adhesion molecules such as NGL-3, TrkC, IL1RAPL1, and Slitrks (Takahashi and Craig, 2013) (Figure 1). The LRRTMs are a family of postsynaptic adhesion molecules with four known members. mTOR inhibitor All contain leucine-rich repeats in the extracellular region, a

single transmembrane domain, and a cytoplasmic region containing a C-terminal PDZ-binding motif that is required for binding to the postsynaptic scaffolding protein PSD-95 (Laurén et al., 2003) (Figure 1). All four LRRTMs are capable of inducing presynaptic differentiation in contacting axons (Linhoff et al., 2009), indicating that they interact with specific presynaptic ligands. Indeed, LRRTM1 and LRRTM2 trans-synaptically interact with neurexins, and these interactions promote excitatory synapse development in a bidirectional manner ( de Wit et al., 2009, Ko et al., 2009 and Siddiqui et al., 2010). However, it has remained unclear whether different LRRTMs

interact with distinct binding partners to promote presynaptic development. Two papers on LRRTM4 reported in Selleckchem Panobinostat this issue of Neuron ( de Wit et al., 2013 and Siddiqui et al., 2013) show that this is the case. These studies demonstrate that LRRTM4 proteins are particularly abundant in the molecular layers of the hippocampal dentate gyrus (DG) and that postsynaptic LRRTM4 trans-synaptically interacts with presynaptic membrane-associated heparan sulfate proteoglycans (HSPGs), such as glypicans and syndecans ( Figure 1). These interactions are HS dependent and promote excitatory, but not inhibitory, synapse development in a bidirectional manner. Knockdown of LRRTM4 in cortical pyramidal neurons by in utero electroporation reduces dendritic spine number and synaptic levels of AMPA-type glutamate receptors (AMPARs) ( de Wit et al., 2013). Moreover, mutant mice that lack LRRTM4 show reductions in the density of dendritic spines and frequency of miniature excitatory postsynaptic currents in the DG but not

CA1 region of the hippocampus ( Siddiqui et al., 2013). Intriguingly, LRRTM4-deficient neurons show impaired activity-dependent Endonuclease trafficking of AMPARs ( Siddiqui et al., 2013), indicating that LRRTM4 may regulate synaptic plasticity. These results show that different LRRTMs display distinct cell-type- and pathway-specific expression patterns and induce presynaptic differentiation through their specific ligands. The new studies also demonstrate that HSPG clustering on axonal surfaces promotes presynaptic differentiation, a function distinct from that of glypicans 4 and 6, which are secreted from astrocytes and promote synaptic AMPAR clustering and excitatory synapse development in retinal ganglion cells (Allen et al., 2012). The new results further indicate that LRRTM4 regulates basal and activity-dependent synaptic localization of AMPARs, consistent with the reported biochemical association of LRRTM4 with AMPARs (Schwenk et al.