Synaptic recognition molecules in development and disease

Abstract

Synaptic connectivity patterns underlie brain functions. How recognition molecules control where and when neurons form synapses with each other, therefore, is a fundamental question of cellular neuroscience. This chapter delineates adhesion and signaling complexes as well as secreted factors that contribute to synaptic partner recognition in the vertebrate brain. The sections follow a developmental perspective and discuss how recognition molecules (1) guide initial synaptic wiring, (2) provide for the rejection of incorrect partner choices, (3) contribute to synapse specification, and (4) support the removal of inappropriate synapses once formed. These processes involve a rich repertoire of molecular players and key protein families are described, notably the Cadherin and immunoglobulin superfamilies, Semaphorins/Plexins, Leucine-rich repeat containing proteins, and Neurexins and their binding partners. Molecular themes that diversify these recognition systems are defined and highlighted throughout the text, including the neuron-type specific expression and combinatorial action of recognition factors, alternative splicing, and post-translational modifications. Methodological innovations advancing the field such as proteomic approaches and single cell expression studies are additionally described. Further, the chapter highlights the importance of choosing an appropriate brain region to analyze synaptic recognition factors and the advantages offered by laminated structures like the hippocampus or retina. In a concluding section, the profound disease relevance of aberrant synaptic recognition for neurodevelopmental and psychiatric disorders is discussed. Based on the current progress, an outlook is presented on research goals that can further advance insights into how recognition molecules provide for the astounding precision and diversity of synaptic connections.

Keywords: Cadherins; Immunoglobulin proteins; Leucine-rich repeat proteins; Neuronal connectivity; Semaphorins; Synapse; Synapse elimination; Synapse specification; Synaptic adhesion; Synaptic recognition.

Fig. 1

Molecular themes that increase the coding power of synaptic recognition factors described in Box 1. (A) The diagram depicts recognition factors expressed during distinct developmental windows. These patterns include transient co-expression, providing for temporally defined functional cooperation. (B) The combinatorial expression of synaptic recognition factors that form multimeric complexes enables them to cooperate. (C) Post-translational modifications such as glycans (green line) can modulate and even enable recognition. (D) Recognition factors can exhibit subcellular localization to different domains of neurites. This cellular targeting defines their synaptic site of action.

Fig. 2

Simplified illustrations of neuronal connectivity in select brain regions. (A) The retina exhibits exemplary laminar organization of cell types and synaptic connections. Rod (grey) and cone (red, green, blue) photoreceptors are located in the outer nuclear layer (ONL). Photoreceptors form synapses with bipolar cells (dark blue) and horizontal cells (dark green) in the outer plexiform layer (OPL). In the inner plexiform layer (IPL), neurites from retinal ganglion cells (RGCs, black), bipolar cells and amacrine cells (light grey) form synapses. (B) In the classic trisynaptic circuit of the hippocampus, dentate gyrus (DG) granule cells receive via the perforant path (PP) inputs from the entorhinal cortex (EC). DG neurons project via mossy fibers (MF) to CA3 pyramidal neurons, which project via Schaffer collaterals (SC) to CA1 pyramidal cells. In one of the additional projections, CA1 pyramidal neurons receive direct inputs from the EC via the temporoammonic (TA) pathway. CA1 pyramidal cells project to the subiculum (Sub) and EC (not shown). (C) Cortical pyramidal neurons (black) receive excitatory inputs from other pyramidal neurons (grey) and in addition subcellularly targeted inhibitory inputs from GABAergic neurons including Parvalbumin-positive (PV) interneurons, Somatostatin (SST)-positive interneurons, and Chandelier cells.

Fig. 3

Recognition molecules that promote synaptic connectivity. (A) Factors promoting recognition and synaptic connections. Pre- and postsynaptic membranes are shown on the left and right, respectively. EphB, EphB receptors; FLRTs, fibronectin LRR transmembrane proteins; GluD2, glutamate receptor delta 2; LAR/RPTPs, LAR-type receptor protein tyrosine phosphatases; LRRTMs, leucine-rich repeat transmembrane proteins; MDGA, MAM domain-containing GPI-anchor proteins; NGLs, Netrin-G ligands; Slitrk, Slit- and Trk-like protein; SynCAMs, Synaptic Cell Adhesion Molecules; Trk, neurotrophin receptor-tyrosine kinase. (B) Domains utilized by the recognition molecules shown in (A). ABD, antibiotic-binding domain-like; C1q, complement component 1q domain; EC, extracellular cadherin domain; EGF, epidermal growth factor; FN, fibronectin; LNS, laminin-neurexin-sex hormone binding globulin domains; LRR, leucine-rich repeat; NHL, ncl-1, HT2A and lin-41 domain; TTR, transthyretin-related domain; YD, tyrosine aspartate repeat.

Fig. 4

Recognition molecules that restrict synaptic connectivity or participate in synapse elimination. (A) Factors restricting synaptic connections. (B) Factors that eliminate synapses once formed. Pre- and post-synaptic membranes are shown on the left and right, respectively. C1q, complement component 1q. (C) Domains utilized by the molecules in (A, B). GAP, GTPase activating domain; GPI, glycosylphosphatidylinositol; IPT, Immunoglobulin-like fold shared by Plexin and transcription factors, LRR, leucine-rich repeat; PSI, Plexin, Semaphorins and Integrin domain; Sema, Semaphorin domain.