Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition

The authors report that neddylation is required for dendritic spine development and stability, and loss of neddylation in excitatory forebrain neurons leads to synaptic loss, impaired neurotransmission, and learning and memory deficits. The roles of neddylation in spine maturation and synaptic trans...

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Bibliographic Details
Published in:	Nature neuroscience Vol. 18; no. 2; pp. 239 - 251
Main Authors:	Vogl, Annette M, Brockmann, Marisa M, Giusti, Sebastian A, Maccarrone, Giuseppina, Vercelli, Claudia A, Bauder, Corinna A, Richter, Julia S, Roselli, Francesco, Hafner, Anne-Sophie, Dedic, Nina, Wotjak, Carsten T, Vogt-Weisenhorn, Daniela M, Choquet, Daniel, Turck, Christoph W, Stein, Valentin, Deussing, Jan M, Refojo, Damian
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-02-2015 Nature Publishing Group
Subjects:	13/109 13/51 13/89 38/1 42/41 42/70 631/378/2597 631/378/2649 631/378/548 631/80/458/2288 64/110 64/60 82/58 9/74 Animal Genetics and Genomics Animals Behavior, Animal - physiology Behavioral Sciences Biological Techniques Biomedicine Brain - growth & development Brain - metabolism Brain mapping Brain research Cognition Disorders - metabolism Dendritic Spines - physiology Disks Large Homolog 4 Protein Genetic aspects Genetic research Guanylate Kinases - physiology Human physical development Membrane Proteins - physiology Mice Mice, Inbred C57BL Mice, Knockout NEDD8 Protein Neurobiology Neurosciences Rats Rats, Sprague-Dawley Synapses - physiology Synaptic Transmission - physiology Ubiquitin-Activating Enzymes - genetics Ubiquitin-Activating Enzymes - physiology Ubiquitin-proteasome system Ubiquitins - antagonists & inhibitors Ubiquitins - metabolism
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Summary:	The authors report that neddylation is required for dendritic spine development and stability, and loss of neddylation in excitatory forebrain neurons leads to synaptic loss, impaired neurotransmission, and learning and memory deficits. The roles of neddylation in spine maturation and synaptic transmission could be attributed to neddylation of PSD-95. Neddylation is a ubiquitylation-like pathway that controls cell cycle and proliferation by covalently conjugating Nedd8 to specific targets. However, its role in neurons, nonreplicating postmitotic cells, remains unexplored. Here we report that Nedd8 conjugation increased during postnatal brain development and is active in mature synapses, where many proteins are neddylated. We show that neddylation controls spine development during neuronal maturation and spine stability in mature neurons. We found that neddylated PSD-95 was present in spines and that neddylation on Lys202 of PSD-95 is required for the proactive role of the scaffolding protein in spine maturation and synaptic transmission. Finally, we developed Nae1 CamKIIα-CreERT2 mice, in which neddylation is conditionally ablated in adult excitatory forebrain neurons. These mice showed synaptic loss, impaired neurotransmission and severe cognitive deficits. In summary, our results establish neddylation as an active post-translational modification in the synapse regulating the maturation, stability and function of dendritic spines.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-6256 1546-1726
DOI:	10.1038/nn.3912