Clustered protocadherins (Pcdhs) are a family of ~60 cadherin‐like proteins (divided into subclasses α, β, and γ) that regulate dendrite morphology and neural connectivity. Their expression is controlled through epigenetic regulation at a gene cluster encoding the molecules. During neural development, Pcdhs mediate dendrite self‐avoidance in some neuronal types through an uncharacterized anti‐adhesive mechanism. Pcdhs are also important for dendritic complexity in cortical neurons likely through a pro‐adhesive mechanism. Pcdhs have also been postulated to participate in synaptogenesis and connectivity. Some synaptic defects were noted in knockout animals, including synaptic number and physiology, but the role of these molecules in synaptic development is not understood. The effect of Pcdh knockout on dendritic patterning may present a confound to studying synaptogenesis. We showed previously that Pcdh‐γs are highly enriched in intracellular compartments in dendrites and spines with localization at only a few synaptic clefts. To gain insight into how Pcdh‐γs might affect synapses, we compared synapses that harbored Pcdh‐γs versus those that did not for parameters of synaptic maturation including pre‐ and postsynaptic size, postsynaptic perforations, and spine morphology by light microscopy in cultured hippocampal neurons and by serial section immuno‐electron microscopy in hippocampal CA1. In mature neurons, synapses immunopositive for Pcdh‐γs were larger in diameter with more frequent perforations. Analysis of spines in cultured neurons revealed that mushroom spines were more frequently immunopositive for Pcdh‐γs at their tips than thin spines. These results suggest that Pcdh‐γ function at the synapse may be related to promotion of synaptic maturation and stabilization.

Clustered protocadherins (Pcdhs) are a large family of ~60 cadherin-like proteins (divided into the subclasses α, β, and γ) that compose a surface "barcode" in individual neurons. The code is generated through combinatorial expression via epigenetic regulation at a large gene cluster that encodes the molecules. During early neural development, Pcdhs were shown to mediate dendrite self-recognition and avoidance in some neuronal types through a still uncharacterized anti-adhesive mechanism. Pcdhs have also been postulated to participate in synaptogenesis and the specificity of connectivity. Some synaptic defects were noted in knockout animals including synaptic number and physiology but the role of these molecules in synaptic development is not understood. We have shown previously that Pcdh-γs are highly enriched in intracellular compartments located in dendrites and spines with less frequent localization at the synaptic membrane. We compared synapses that expressed endogenous Pcdh-γs versus those that did not for parameters of synaptic maturation including pre-and postsynaptic punctum size, postsynaptic perforations and spine morphology in mature cultured hippocampal neurons. We also performed serial section immuno-electron microscopy in intact hippocampal CA1 and measured synaptic size and perforation status of Pcdh-γ positive and negative synapses. At both the light and ultrastructural levels, synapses immunopositive for Pcdh-γs were found to be larger in diameter with more frequent perforations. Analysis of spines in cultured neurons revealed that mushroom spines were more frequently immunopositive for Pcdh-γs at their tips than thin spines. Taken together, these results suggest that Pcdh-γ function at the synapse may be related to synaptic maturation and stabilization.