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 ␥-protocadherins (␥-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-␥-null, we find that astrocyte-neuron ␥-Pcdh contacts are critical for synaptogenesis in developing cultures. Synaptogenesis can eventually proceed among neurons cocultured with Pcdh-␥-null astrocytes, but only if these neurons themselves express the ␥-Pcdhs. Consistent with this, restricted mutation of the Pcdh-␥ 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.

Combinatorial homophilic interaction between γ-protocadherin multimers greatly expands the molecular diversity of cell adhesion

“…This has important implications for any potential role for γ-Pcdhs in the control of synaptic specificity, which remains to be demonstrated but would be consistent with some (although not all; see ref. 11) extant functional data in vivo (9,10,12,13,46). Several reports indicate that single neurons of the same cell type can express different subsets of clustered Pcdh isoforms (4,8,(46)(47)(48).…”

“…An increase in neuronal apoptosis is also observed in the postnatal retina (11) and hypothalamus (12) when the γ-Pcdhs are disrupted using a conditional allele. Crossing null mutants with Bax −/− mice rescues neurodegeneration but not synapse density, indicating a primary role for the γ-Pcdhs in synaptogenesis (9), in part through mediation of perisynaptic astrocyte-neuron contacts (13).…”

ALCAM Regulates Mediolateral Retinotopic Mapping in the Superior Colliculus

“…Images were captured on a Leica DM5000B epifluorescence microscope using nonoverlapping ET series filters (Chroma Technology). For in situ hybridization to detect ALCAM or L1 mRNA, sense and antisense probes were generated from psBluescript SK plasmid containing mouse L1 cDNA (Macias et al, 2002) or a 900 bp fragment of mouse ALCAM cDNA (Weiner et al, 2004), and hybridization was performed using digoxigenin-labeled probes as described previously (Bartsch et al, 1994;Garrett and Weiner, 2009).…”

Morphological plasticity of astroglia: Understanding synaptic microenvironment

“…These mechanisms have been implicated when observing patients with autism, a disease linked to mutations in neuroligins and neurexins (Bernardinelli et al, 2014a; Chih et al, 2005). Other adhesive molecules that have been involved in neuron‐astrocyte binding and that might be involved in boosting PAP morphogenesis are Ng‐CAM (Grumet et al, 1984), SynCAM1 (Sandau et al, 2012), NCAM (Theodosis et al, 2004), and protocadherin‐gammaC5 (Garrett and Weiner, 2009; Li et al, 2010). However, whether and how these signaling molecules and their partners or ligands act within PAPs in organized tissue in situ remains to be established.…”