Leucine-rich repeat-containing synaptic adhesion molecules as organizers of synaptic specificity and diversity

Abstract

The brain harbors billions of neurons that form distinct neural circuits with exquisite specificity. Specific patterns of connectivity between distinct neuronal cell types permit the transfer and computation of information. The molecular correlates that give rise to synaptic specificity are incompletely understood. Recent studies indicate that cell-surface molecules are important determinants of cell type identity and suggest that these are essential players in the specification of synaptic connectivity. Leucine-rich repeat (LRR)-containing adhesion molecules in particular have emerged as key organizers of excitatory and inhibitory synapses. Here, we discuss emerging evidence that LRR proteins regulate the assembly of specific connectivity patterns across neural circuits, and contribute to the diverse structural and functional properties of synapses, two key features that are critical for the proper formation and function of neural circuits.

Fig. 1. LRR proteins regulate synapse development in CA1 pyramidal neurons.

Symmetric CA1 synapses. Slitrk3 regulates density, pre-synaptic bouton size, and ultrastructural organization of inhibitory synapses formed on CA1 pyramidal cell bodies and in CA1 stratum radiatum (SR), presumably by local GABAergic interneurons (green). CA3-CA1 SC synapses. Different LRR proteins regulate synapse density on the proximal apical dendritic segment, where Schaffer collateral (SC) axons synapse onto CA1 neurons (black). NGL-2, SALM1, and SALM3 positively regulate dendritic spine density, whereas SALM4 negatively regulates SC spine density. LRRTM1, SALM1, and SALM4 influence synapse structure or ultrastructure. LRRTM1 loss results in longer, possibly less mature, spines, as well as a dispersion of vesicles in the pre-synaptic bouton. SALM1 loss results in odd-looking spines with thin protrusions emerging from the spine heads, as well as a decrease in post-synaptic density (PSD) length and an increase in the proportion of perforated synapses. SALM4 loss results in an increase in PSD length. LRRTM1/2, NGL-2, and SALM1 affect short- or long-term synaptic plasticity. Loss of LRRTM1/2 results in a long-term potentiation (LTP) block. Loss of SALM1 results in enhanced LTP. Loss of netrin-G2, the pre-synaptic binding partner of NGL-2, also results in enhanced LTP as well as facilitation of post-tetanic potentiation (PTP). EC-CA1 TA synapses. At temporoammonic (TA) synapses, formed on distal CA1 dendrites by incoming afferents from layer III (LIII) entorhinal cortex (EC) neurons, NGL-1 KO results in attenuation of PTP. Loss of the pre-synaptic binding partner of NGL-1, netrin-G1, at TA synapses also results in attenuated LTP

Fig. 2. LRR proteins regulate synapse development in dentate gyrus granule cells.

LPP-DG synapses. Lateral perforant path (LPP) axons from layer II (LII) lateral EC (LEC) synapse on distal dentate gyrus (DG) granule cell dendrites in the outer molecular layer (OML). Loss of LRRTM4 results in a reduction in spine density at LPP-DG synapses. MPP-DG synapses. Medial perforant path (MPP) synapses form between incoming LII medial EC (MEC) afferents and DG granule cell dendrites in the middle molecular layer (MML). At MPP-DG synapses, loss of FLRT3 or LRRTM3 results in a reduction in spine density. Loss of NGL-2, or its pre-synaptic binding partner, netrin-G2, results in an increase in the paired-pulse ratio (PPR) that corresponds to an attenuated paired-pulse depression (PPD)

Fig. 3. LRR proteins mediate functional wiring of retinal synapses.

a Synaptic wiring in the outer plexiform layer. Photoreceptors (PR) form triad synapses with horizontal cells (HC) and bipolar cells (BC) in the outer plexiform layer (OPL). NGL-2 localizes to HC axon tips, which synapse onto netrin-G2-expressing rod PRs. NGL-2 KO causes HC axons to overshoot their laminar target, the OPL, and form fewer synapses with rod PRs, while HC dendrite—cone PR synapses that do not contain NGL-2 are unaffected. Elfn1 is expressed by rod PRs, which synapse onto ON-BCs in the OPL. Neighboring cone PR synapses formed on ON-BCs do not express Elfn1. Synaptic targeting of Elfn1 is mediated by α2δ4, an auxiliary subunit of the Cav1.4 channel. Once at the synapse, Elfn1 bridges a trans-synaptic complex between pre-synaptic, glutamate release-directing Cav1.4, and post-synaptic, glutamate-sensing mGluR6. Elfn1 KO in rod PRs disrupts the formation of rod PR synapses on ON-BCs, while neighboring cone PR synapses on ON-BCs are unaffected. b Laminar targeting in the inner plexiform layer. FLRT2 may mediate sublaminar targeting in the inner plexiform layer (IPL). FLRT2 protein is highly expressed in sublaminae (S) 2 and 4 of the IPL, where the dendrites of both starburst amacrine cells (SACs) and direction-selective ganglion cells (DSGCs) arborize. Unc5c is expressed in a complementary pattern in S1/3/5 of the IPL. FLRT2-expressing neurons are repelled by Unc5c in vitro, suggesting that Unc5c might restrict FLRT2-positive SAC and DSGC dendrites to S2/4 of the developing IPL. ONL outer nuclear layer, OPL outer plexiform layer, INL inner nuclear layer, IPL inner plexiform layer, GCL ganglion cell layer