Neddylation regulates excitatory synaptic transmission and plasticity

Abstract

Post-translational modifications, like phosphorylation, ubiquitylation, and sumoylation, have been shown to impact on synaptic neurotransmission by modifying pre- and postsynaptic proteins and therefore alter protein stability, localization, or protein-protein interactions. Previous studies showed that post-translational modifications are essential during the induction of synaptic plasticity, defined by a major reorganization of synaptic proteins. We demonstrated before that neddylation, a post-translational modification that covalently binds Nedd8 to lysine-residues, strongly affects neuronal maturation and spine stability. We now analysed the consequences of inhibiting neddylation on excitatory synaptic transmission and plasticity, which will help to narrow down possible targets, to make educated guesses, and test specific candidates. Here, we show that acute inhibition of neddylation impacts on synaptic neurotransmission before morphological changes occur. Our data indicate that pre- and postsynaptic proteins are neddylated since the inhibition of neddylation impacts on presynaptic release probability and postsynaptic receptor stabilization. In addition, blocking neddylation during the induction of long-term potentiation and long-term inhibition abolished both forms of synaptic plasticity. Therefore, this study shows the importance of identifying synaptic targets of the neddylation pathway to understand the regulation of synaptic transmission and plasticity.

Synaptic control of DNA methylation involves activity-dependent degradation of DNMT3A1 in the nucleus

“…4b, c). Moreover, the expression of late-LTP is neddylation-sensitive and field excitatory postsynaptic potentiation slope values returned to baseline within three hours when the slices were treated with the NEDD8 inhibitor MLN4924 like reported previously [37] (Fig. 4d-f).…”

Neddylation is required for presynaptic clustering of mGlu7 and maturation of presynaptic terminals

“…However, the function and regulatory machinery of neddylation in the brain remain largely unknown. Recent studies have demonstrated that inhibition of neddylation reduces synaptic maturation, basal synaptic transmission, presynaptic release probability, postsynaptic AMPA and NMDA currents, surface expression of AMPA receptors, synaptic plasticity (both long-term potentiation and long-term depression), and cognitive functions 14 , 17 , 31 , 32 . While PSD-95 was previously identified as a critical substrate of neddylation in postsynaptic spines, in this study, we demonstrated that presynaptic mGlu7 is a target of neddylation, and inhibition of neddylation reduces the clustering of mGlu7 to the presynaptic active zone and reduces the maturation of excitatory presynaptic terminals.…”

“…Neddylation enhances the activity of cullin-RING Ub ligases (CRLs), leading to the ubiquitination and subsequent degradation of their substrates, which are involved in multiple biological processes, including cell cycle progression 13 . Although NEDD8 was first identified in the brain, very few neddylation substrates, including PSD-95, cofilin/actin-depolymerizing factor (ADF), parkin, and PINK, have been identified in neurons 14 – 18 . A recent elegant study revealed that neddylation is essential for clustering of the dendrite scaffold protein PSD-95 and is necessary for dendritic spine stability and maturation 17 .…”

Ubiquitin and Ubiquitin-Like Proteins in the Critical Equilibrium between Synapse Physiology and Intellectual Disability

“…However, inhibition of the neddylation pathway does not enhance synaptic activity and strength as it would have been expected as a consequence of reduced synaptic ubiquitination. Instead, it destabilizes dendritic spines, affects synaptic transmission and plasticity, and impairs cognitive functions (Scudder and Patrick, 2015;Vogl et al, 2015;Brockmann et al, 2019), thus suggesting that neuronal neddylation targets other substrates relevant to synaptic function. In line with this, Vogl and colleagues elegantly demonstrated that PSD-95 is neddylated at K202 by MDM2 (Vogl et al, 2015), which also mediates PSD-95 ubiquitination ( Fig.…”