Control of CNS Synapse Development by γ-Protocadherin-Mediated Astrocyte–Neuron Contact

Abstract

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 γ-protocadherins (γ-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 arePcdh-γ-null, we find that astrocyte–neuron γ-Pcdh contacts are critical for synaptogenesis in developing cultures. Synaptogenesis can eventually proceed among neurons cocultured withPcdh-γ-null astrocytes, but only if these neurons themselves express the γ-Pcdhs. Consistent with this, restricted mutation of thePcdh-γ cluster in astrocytesin vivosignificantly delays both excitatory and inhibitory synapse formation. Together, these results identify the first known contact-dependent mechanism by which perisynaptic astrocyte processes promote synaptogenesis.