Table 1.

Synaptogenic molecules secreted by astrocytes

Synaptogenic molecule	Key binding partner (or partners)	Effect in vitro	Effect in vivo
Brain-derived neurotrophic factor (BDNF)	Neuronal neuregulin 1 and glial ERBB receptor interactions. Activation of glial ERBB receptors in response to neuronally derived neuregulin 1 induced glia to produce trophic factors such as BDNF		Transgenic elimination of ERBB receptors in the glia of the vestibular sensory epithelium reduced the number of excitatory synapses between hair cells and sensory neurons by 82% and led to vestibular defects. Similarly, BDNF expression was reduced in the glia of the vestibular system of ERBB-deficient mice. Restoration of BDNF expression in these cells rescued synapse formation and the vestibular deficits116
Cholesterol	Apolipoprotein E delivers cholesterol to neurons	Addition of cholesterol to retinal ganglion cells (RGCs) increased the number of excitatory synapses by 69% and increased presynaptic vesicle release 12-fold. Cholesterol is thought to act as a building material to enhance dendrite and presynaptic terminal differentiation10,33
Ephrins	EPH receptor tyrosine kinase	Ephrin–EPH interactions modulate dendritic spine dynamics. Activation of the receptor EPH type A4 (EPHA4) by ephrin A3 induces spine retraction, whereas inhibition of ephrin–EPHA4 interactions distorted spine shape and organization69,70	EPHA4- and ephrin A3-knockout mice showed irregularities in the morphology of their dendritic spines69,70
Glypican	Unknown	Glypicans converted silent synapses to functional ones by increasing the amplitude and frequency of glutamatergic synaptic events in cultured RGCs. This conversion was achieved by increasing the surface level of AMPA receptors1	Genetic deletion of glypicans in vivo led to defective synapse formation, with decreased amplitude of excitatory synaptic currents and reduced recruitment of AMPA receptors1
Hevin	Neuroligins and neurexins (S. Singh, A. Pamukcu and C. Eroglu, personal communication)	Addition of hevin to astrocyte-free RGC cultures significantly increased the number of postsynaptically silent excitatory synapses4	At postnatal day 14 (P14), the number of synapses in the superior colliculus was 35% less in hevin-null brains than in wild-type brains4 Hevin controls the size of synapses. In hevin-null brains, the area of excitatory synapses was smaller than in wild-type brains4
SPARC	Integrins39	SPARC is not synaptogenic but specifically antagonized the synaptogenic function of hevin4	At P14, SPARC-null mice had around a 70% increase in the number of vesicular glutamate transporter 2- and postsynaptic density 95-positive synapses at the superior colliculus in comparison with wild-type mice4
Thrombospondins (TSPs)	α2δ-1 voltage-gated calcium channel subunit. Gabapentin, the high affinity ligand for α2δ-1, inhibits TSP-induced synapse formation in cultured RGCs35. Injection of gabapentin during the first postnatal week (the active stage of synapse formation) decreased the number of excitatory synapses in the cerebral cortex35 Neuroligin 1 is a trans-synaptic adhesion molecule. Acceleration of synapse formation in cultured hippocampal neurons occurred by TSP binding to and clustering neuroligin 1 (REF. 28) Integrins37	Addition of TSP to astrocyte-free RGC cultures increased the number of postsynaptically silent excitatory synapses2 TSP1 accelerated excitatory synapse formation in hippocampal neuronal cultures but did not increase the final number of synapses28	In the TSP1 and TSP2 double-null cerebral cortex, synaptic puncta were decreased by 40% at P8 and by 25% at P21 compared with wild-type controls2
Transforming growth factor β1 (TGFβ1)	TGFβ receptor type II	Addition of TGFβ1 to cultured cortical neurons increased the number of excitatory synapses by 150%. TGFβ1 was reported to induce synapse formation by increasing the release of the NMDA receptor co-agonist D-serine. Inhibition of NMDA receptors or knocking down serine racemase to inhibit the conversion of L-serine to D-serine inhibited TGFβ1-induced synapse formation29