title: An essential role for UBE2A/HR6A in learning and memory and mGLUR-dependent long-term depression.
abstract: UBE2A deficiency syndrome (also known as X-linked intellectual disability type Nascimento) is an intellectual disability syndrome characterized by prominent dysmorphic features, impaired speech and often epilepsy. The syndrome is caused by Xq24 deletions encompassing the UBE2A (HR6A) gene or by intragenic UBE2A mutations. UBE2A encodes an E2 ubiquitin-conjugating enzyme involved in DNA repair and female fertility. A recent study in Drosophila showed that dUBE2A binds to the E3 ligase Parkin, which is required for mitochondrial function and responsible for juvenile Parkinson's disease. In addition, these studies showed impairments in synaptic transmission in dUBE2A mutant flies. However, a causal role of UBE2A in of cognitive deficits has not yet been established. Here, we show that Ube2a knockout mice have a major deficit in spatial learning tasks, whereas other tested phenotypes, including epilepsy and motor coordination, were normal. Results from electrophysiological measurements in the hippocampus showed no deficits in synaptic transmission nor in the ability to induce long-term synaptic potentiation. However, a small but significant deficit was observed in mGLUR-dependent long-term depression, a pathway previously implied in several other mouse models for neurodevelopmental disorders. Our results indicate a causal role of UBE2A in learning and mGLUR-dependent long-term depression, and further indicate that the Ube2a knockout mouse is a good model to study the molecular mechanisms underlying UBE2A deficiency syndrome.
authors.affiliation: Department of Neuroscience, ENCORE Expertise Centre for Neurodevelopmental Disorders, and.
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Bruinsma
authors.affiliation: Department of Neuroscience.
authors.forename: Sanne M C
authors.initials: SM
authors.lastname: Savelberg
authors.affiliation: Department of Neuroscience.
authors.forename: Martijn J
authors.initials: MJ
authors.lastname: Kool
authors.affiliation: Department of Neuroscience.
authors.forename: Mehrnoush Aghadavoud
authors.initials: MA
authors.lastname: Jolfaei
authors.affiliation: Department of Neuroscience, ENCORE Expertise Centre for Neurodevelopmental Disorders, and.
authors.forename: Geeske M
authors.initials: GM
authors.lastname: Van Woerden
authors.affiliation: Department of Developmental Biology, Erasmus MC, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands.
authors.forename: Willy M
authors.initials: WM
authors.lastname: Baarends
authors.affiliation: Department of Neuroscience, ENCORE Expertise Centre for Neurodevelopmental Disorders, and y.elgersma@erasmusmc.nl.
authors.forename: Ype
authors.initials: Y
authors.lastname: Elgersma
mesh_terms: D000818:Animals; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D006624:Hippocampus / Q000502:physiology; D008607:Intellectual Disability / Q000235:genetics; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009473:Neuronal Plasticity / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012919:Social Behavior; D009435:Synaptic Transmission / Q000502:physiology; D044763:Ubiquitin-Conjugating Enzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018094:Receptors, Metabotropic Glutamate; C512786:Ube2a protein, mouse; D044763:Ubiquitin-Conjugating Enzymes