Control of CNS Synapse Development by γ-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.