Table 1.

Major secreted or cell adhesion proteins implicated in genesis of glutamatergic and GABAergic synapses^a

Synaptogenic protein [Refs]	Key binding partner	Family members and related proteins	Effect of bath addition, coculture, bead presentation or overexpression in neurons	Effect of targeted deletion in vivo, or of knock-down or dominant-negative forms in culture
Wnt7a [18]	Frizzled	>16 Wnts 10 Frizzleds	Addition induced axon morphological change and synaptic vesicle clustering	Wnt7a−/− transiently reduced complexity and synapsin I content of glomerular rosettes between cerebellar mossy fibers at P8–P9 but not ≥P10
FGF22 [21]	FGFR2	>20 FGFRs 4 FGFs	Addition induced axon branching and presynaptic specializations	FGFR2−/− reduced number and size of synapsin aggregates in the cerebellar granule layer FGFR2 soluble blocking reagents reduced number and size of synaptophysin-YFP aggregates in the cerebellar granule layer
TSPs 1 and 2 [22]	Several possible	5 TSPs	Addition to glia-free culture induced postsynaptically silent synapses	(TSP1,2)−/− reduced numbers of SV2 puncta and opposed SAP102–bassoon puncta in cortex
N-cadherin [65,138,139]	N-cadherin	5 Classical cadherins 12 Atypical cadherins >52 Protocadherins	Overexpression had no effect on spine morphology or density in culture	Dominant-negative form reduced numbers of synapsin, FM-dye, GAD and PSD95 puncta more effectively at 1 week than at 3 weeks in hippocampal culture β-Catenin−/− reduced presynaptic content of non-docked vesicles and response to prolonged repetitive lowfrequency stimulation at hippocampal CA1 synapses; increased length of synaptophysin–GFP but not bassoon or PSD95–GFP puncta in hippocampal culture α-N-catenin−/− increased dendritic protrusion length and motility
Neuroligins [41,55,59–61]	Neurexins	4 Neuroligins	Coculture or beads induced local glutamatergic and GABAergic presynaptic specializations Overexpression increased presynaptic input Moderate-level expression increased functional synapses	RNAi knock-down of Nlg-1,2,3 in hippocampal culture reduced numbers of spines, VGlut1, GluR1 and VGAT puncta, and reduced mPSC amplitude and frequency; presumed mIPSC reduced most Mislocalized overexpression of Nlg-2 in hippocampa lculture reduced number and size of gephyrin, GABAAR, PSD95 and NMDAR puncta, and reduced mIPSC and mEPSC frequency and amplitude
β-Neurexin1 [60,62,66]	Neuroligins	3β-Neurexins 3α-Neurexins Extensive alternative splicing	Coculture or beads induced local glutamatergic and GABAergic postsynaptic specializations (clustering of PSD95, NMDAR, gephyrin and GABAAR)	(α-Neurexin-1, −2, −3)−/− (without disruption of β-neurexins) reduced numbers of GABAergic but not glutamatergic synapses, reduced N-type Ca2+ channel function, reduced spontaneous transmitter release, and greatly reduced evoked transmission in neonatal brainstem and cultured cortical slices
SynCAM1 [29,140]	SynCAMs	4 SynCAMs 4 Nectins	Coculture induced local glutamatergic presynaptic specializations Overexpression increased functional synaptic inputs	Dominant-negative construct against SynCAMs and neurexins reduced number and size of FM-dye puncta in hippocampal culture
Ephrin-B1 [71,74,116,141]	EphBs	5 A-ephrins 3 B-ephrins 9 EphA receptors 5 EphB receptors	Addition of clustered B-ephrins induced clustering of EphB and NMDAR, and enhanced spine morphogenesis	Ephrin-B2−/− had no effect on number of synapses or NMDAR content in hippocampal CA1 region EphB2−/− reduced NMDAR content and NMDAR-mediated currents but had no effect on spine density in Hippocampus (EphB-1, −2, −3)−/− reduced number and size of spines and PSD area in hippocampal CA3region; increased length of dendritic protrusions, caused loss of spine heads and reduced NMDAR and AMPAR content in hippocampal culture
NARP [67–69]	AMPA receptors	NP1, NPR	Coculture induced local AMPAR clustering and cell-type-specific NMDAR clustering Overexpression increased cell-type-specific glutamatergic synaptogenesis	Dominant-negative form reduced number of AMPAR and synaptophysin clusters but not gephyrin of GAD clusters in spinal cord culture; reduced number of AMPAR and NMDAR clusters on hippocampal interneurons but not pyramidal neurons

^aAbbreviations: AMPAR, AMPA receptor; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; GABA_AR, GABA_A receptor; mEPSC, miniature excitatory postsynaptic current; mIPSC, miniature inhibitory postsynaptic current; mPSC, miniature postsynaptic current; NARP, neuronal activity-regulated pentraxin; NMDAR, NMDA receptor; NPR, neuronal pentraxin receptor; P, postnatal day; TSPs, thombospondins; VGAT, vesicular GABA transporter; VGlut1, vesicular glutamate transporter1; YFP, yellow fluorescent protein.