An opposing function of paralogs in balancing developmental synapse maturation

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.

Astrocyte lineage cells are essential for functional neuronal differentiation and synapse maturation in human iPSC‐derived neural networks

“…With thrombospondin-1 incubation, we did not observe a significant change in the dendritic density of mature glutamatergic synapses (Figure 8d-f). This is in line with the idea that thrombospondin-1 induces immature silent synapses without AMPA receptors (Christopherson et al, 2005), which have been described to be stabilized in the immature state by PSD93, whereas PSD95 promotes their unsilencing (Favaro et al, 2018;Huang et al, 2015). In summary, our results demonstrate that the astrocyte-derived synapse maturation inducer cholesterol also enhances synapse maturation in astrocyte lineage cell-depleted hiPSC neural cultures.…”

Shank2 expression identifies a subpopulation of glycinergic interneurons involved in nociception and altered in an autism mouse model

“…Recently, the genetic diversity of these populations has been demonstrated to be extensive and a large number of subpopulations have been identified in a single-cell transcriptome study (Häring et al, 2018). Nevertheless, neuronal physiology is highly influenced by the quantity and quality of their synaptic inputs, which is strongly dependent upon the composition and architectural organization of post-synaptic structures (Schlüter et al, 2006;Favaro et al, 2018). Therefore, a distinct layer of diversity may be identified once the synaptic composition of neuronal subtypes is taken into consideration.…”

Cocaine Triggers Glial-Mediated Synaptogenesis

“…This implies another potential cellular trait of these synapses, namely, low levels of PSD95 and other synaptic scaffolds. PSD95 functions to stabilize AMPARs at mature synapses, while genetic deletion or knockdown of PSD95 increases the level of AMPAR-silent synapses, potentially resulting from increased lability of AMPARs (Beique et al, 2006;Favaro et al, 2018;Shukla et al, 2017). At the signaling level, TSP-α2δ-1-mediated synaptogenesis in developing cortical neurons requires the small GTPase Rac1 (Risher et al, 2018).…”