The primate-specific peptide Y-P30 regulates morphological maturation of neocortical dendritic spines.

Janine R Neumann,Kay Jüngling,Petra Wahle,Michael R Kreutz,Mohammad I K Hamad,Suvarna Dash-Wagh,Andrea Räk,Alexander Jack,Hans-Christian Pape,Martin Puskarjov

doi:10.1371/journal.pone.0211151

Abstract

The 30-amino acid peptide Y-P30 corresponds to the N-terminus of the primate-specific, sweat gland-derived dermcidin prepropeptide. Previous work has revealed that Y-P30 enhances the interaction of pleiotrophin and syndecans-2/3, and thus represents a natural ligand to study this signaling pathway. In immature neurons, Y-P30 activates the c-Src and p42/44 ERK kinase pathway, increases the amount of F-actin in axonal growth cones, and promotes neuronal survival, cell migration and axonal elongation. The action of Y-P30 on axonal growth requires syndecan-3 and heparan sulfate side chains. Whether Y-P30 has the potential to influence dendrites and dendritic protrusions has not been explored. The latter is suggested by the observations that syndecan-2 expression increases during postnatal development, that syndecan-2 becomes enriched in dendritic spines, and that overexpression of syndecan-2 in immature neurons results in a premature morphological maturation of dendritic spines. Here, analysing rat cortical pyramidal and non-pyramidal neurons in organotypic cultures, we show that Y-P30 does not alter the development of the dendritic arborization patterns. However, Y-P30 treatment decreases the density of apical, but not basal dendritic protrusions at the expense of the filopodia. Analysis of spine morphology revealed an unchanged mushroom/stubby-to-thin spine ratio and a shortening of the longest decile of dendritic protrusions. Whole-cell recordings from cortical principal neurons in dissociated cultures grown in the presence of Y-P30 demonstrated a decrease in the frequency of glutamatergic mEPSCs. Despite these differences in protrusion morphology and synaptic transmission, the latter likely attributable to presynaptic effects, calcium event rate and amplitude recorded in pyramidal neurons in organotypic cultures were not altered by Y-P30 treatment. Together, our data suggest that Y-P30 has the capacity to decelerate spinogenesis and to promote morphological, but not synaptic, maturation of dendritic protrusions.

Highlights

A distinctive feature of the primate cerebral cortex among mammals is a large number of supranumerary synapses
Overexpression of syndecan-2 for seven days in immature embryonically dissociated hippocampal neurons results in an acceleration of morphological maturation of spines starting from preexisting filopodia: The fraction of protrusions with heads, aka mature-like spines, increases from 20–25% in control to 75%, a value normally seen in DIV 30 hipoocampal cultures; the protrusions become shorter indicating a higher degree of maturity [17]
To exclude that the latter could have been a false negative result due to the immaturity of neurons in short-term culture we assessed the effects of Y-P30 exposure of postnatal rat cortical organotypic culture (OTC) grown from DIV 0–5, DIV 7–10, and DIV 15–20 with Y-P30 in the medium

Summary

Introduction

A distinctive feature of the primate cerebral cortex among mammals is a large number of supranumerary synapses. In the human prefrontal cortex, for instance, overproduction and elimination of dendritic spines and synaptic sites continues into the third decade of life [1, 2]. Syndecan-3 is enriched on axons, and Y-P30 has been shown to promote axonal growth in a syndecan-3-dependent and heparan-sufate side chaindependent manner in cortical stem cell-derived neurons, and in days-in-vitro (DIV) 3–4 retinal and cortical microexplants [11,12,13]. Syndecan-2 becomes phosphorylated by EphB2 and signals via the calcium/calmodulin-dependent serine kinase (CASK) to trigger the transformation of filopodia into mature spines [17,18,19,20,21]

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