Gamma-protocadherin localization at the synapse corresponds to parameters of synaptic maturation

Abstract

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.

Protocadherins at the Crossroad of Signaling Pathways

“…Later, cPcdh trafficking was speculated to be involved in self-avoidance. According to the latter hypothesis, cPcdh-mediated matching between cell surfaces might induce endolysosomal trafficking of adhesive molecules, leading to the transition from transmembrane adhesion to detachment ( Phillips et al, 2017 ; LaMassa et al, 2019 ).…”

Clustered Protocadherins Emerge as Novel Susceptibility Loci for Mental Disorders

“…Significant progress has been made on cell-surface delivery mechanisms of cPcdhs. In particular, Pcdhγ proteins are initially detected in the cytoplasm as a mobile pool and their cell-surface delivery corresponds to the maturation of synapses ( Fernandez-Monreal et al, 2009 , 2010 ; LaMassa et al, 2020 ). For example, Pcdhγa3 and Pcdhγb2 form juxtanuclear membrane tubules in the cytoplasm when overexpressed ( Hanson et al, 2010 ).…”