Control of CNS synapse development by {gamma}-protocadherin-mediated astrocyte-neuron contact.
Recent studies indicate that astrocytes, whose processes enwrap synaptic terminals, promote synapse formation both by releasing soluble factors and through contact-dependent mechanisms. Although astrocyte-secreted synaptogenic factors have been identified, the molecules underlying perisynaptic astroctye-neuron contacts are unknown. Here we show that the gamma-protocadherins (gamma-Pcdhs), a family of 22 neuronal adhesion molecules encoded by a single gene cluster, are also expressed by astrocytes and localize to their perisynaptic processes. Using cocultures in which either astrocytes or neurons are Pcdh-gamma-null, we find that astrocyte-neuron gamma-Pcdh contacts are critical for synaptogenesis in developing cultures. Synaptogenesis can eventually proceed among neurons cocultured with Pcdh-gamma-null astrocytes, but only if these neurons themselves express the gamma-Pcdhs. Consistent with this, restricted mutation of the Pcdh-gamma cluster in astrocytes in vivo significantly delays both excitatory and inhibitory synapse formation. Together, these results identify the first known contact-dependent mechanism by which perisynaptic astrocyte processes promote synaptogenesis.
Department of Biology, The University of Iowa, Iowa City, 52242, USA.
Andrew M
AM
Garrett
Joshua A
JA
Weiner
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000502:physiology*; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000502:physiology*; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009154:Mutation; D009474:Neurons / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000196:embryology / Q000254:growth & development / Q000502:physiology*; D013569:Synapses / Q000502:physiology*
D000070585:Cadherin Related Proteins; D015820:Cadherins; D017077:Culture Media, Conditioned; C464785:Gamma-protocadherins