An opposing function of paralogs in balancing developmental synapse maturation.

Plinio D Favaro,Lei Cui,Xiaojie Huang,Siegrid Löwel,Yan Dong,Karl-Alexander Engelhardt,Oliver M Schlüter,Leon Hosang,Frank Schmitz,Sophia Stodieck,Yu-Zhang Liu

doi:10.1371/journal.pbio.2006838

Abstract

The disc-large (DLG)–membrane-associated guanylate kinase (MAGUK) family of proteins forms a central signaling hub of the glutamate receptor complex. Among this family, some proteins regulate developmental maturation of glutamatergic synapses, a process vulnerable to aberrations, which may lead to neurodevelopmental disorders. As is typical for paralogs, the DLG-MAGUK proteins postsynaptic density (PSD)-95 and PSD-93 share similar functional domains and were previously thought to regulate glutamatergic synapses similarly. Here, we show that they play opposing roles in glutamatergic synapse maturation. Specifically, PSD-95 promoted, whereas PSD-93 inhibited maturation of immature α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid–type glutamate receptor (AMPAR)–silent synapses in mouse cortex during development. Furthermore, through experience-dependent regulation of its protein levels, PSD-93 directly inhibited PSD-95’s promoting effect on silent synapse maturation in the visual cortex. The concerted function of these two paralogs governed the critical period of juvenile ocular dominance plasticity (jODP), and fine-tuned visual perception during development. In contrast to the silent synapse–based mechanism of adjusting visual perception, visual acuity improved by different mechanisms. Thus, by controlling the pace of silent synapse maturation, the opposing but properly balanced actions of PSD-93 and PSD-95 are essential for fine-tuning cortical networks for receptive field integration during developmental critical periods, and imply aberrations in either direction of this process as potential causes for neurodevelopmental disorders.

Highlights

The postsynaptic density (PSD) is a proteinaceous network that regulates and coordinates the signaling of multiple receptors and other proteins in a confined region at the synapse, including developmental changes, to reach its mature functionality
Focusing on PSD-95, a core protein of the glutamate receptor signaling complex, we recently demonstrated that PSD-95–dependent maturation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptor (AMPAR)-silent synapses ends the critical period of the juvenile form of ocular dominance (OD) plasticity (ODP) in the visual cortex [8], a classical model for experiencedependent critical period plasticity [9,10,11]
While loss of PSD-95 prevented the developmental decrease in silent synapses, the effect of loss of the fraction of silent synapses declines faster (PSD-93) was opposite by accelerating this developmental decrease

Summary

Introduction

The postsynaptic density (PSD) is a proteinaceous network that regulates and coordinates the signaling of multiple receptors and other proteins in a confined region at the synapse, including developmental changes, to reach its mature functionality. Paralogs either adapted for specific requirements of different cellular compartments or organs, such as the liver- or heart-specific lactate dehydrogenases, or evolved more specialized functions in the same compartment, such as the opsins for color vision in photoreceptor cells [4,5]. It remains elusive whether the multiple paralogous proteins of the PSD functionally interact within the same synapse or each individually predominates in different synapses. Given the similar cytoarchitecture of functional domains of the neocortex, mechanistic insights into sensory cortical phenotypes likely translate to pathomechanisms of mental disorders

Results

Discussion

Conclusion