title: The anaphase promoting complex is required for memory function in mice.
abstract: Learning and memory processes critically involve the orchestrated regulation of de novo protein synthesis. On the other hand it has become clear that regulated protein degradation also plays a major role in neuronal plasticity and learning behavior. One of the key pathways mediating protein degradation is proteosomal protein destruction. The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets proteins for proteosomal degradation by the 26S proteasome. While the APC/C is essential for cell cycle progression it is also expressed in postmitotic neurons where it has been implicated with axonal outgrowth and neuronal survival. In this study we addressed the role of APC/C in learning and memory function by generating mice that lack the essential subunit APC2 from excitatory neurons of the adult forebrain. Those animals are viable but exhibit a severe impairment in the ability to extinct fear memories, a process critical for the treatment of anxiety diseases such as phobia or post-traumatic stress disorder. Since deregulated protein degradation and APC/C activity has been implicated with neurodegeneration we also analyzed the effect of Apc2 deletion in a mouse model for Alzheimer's disease. In our experimental setting loss of APC2 form principle forebrain neurons did not affect the course of pathology in an Alzheimer's disease mouse model. In conclusion, our data provides genetic evidence that APC/C activity in the adult forebrain is required for cognitive function.
authors.affiliation: Laboratory for Aging and Cognitive Diseases, European Neuroscience Institute, Göttingen D-37077, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuczera
authors.forename: Roman Manuel
authors.initials: RM
authors.lastname: Stilling
authors.forename: Hung-En
authors.initials: HE
authors.lastname: Hsia
authors.forename: Sanaz
authors.initials: S
authors.lastname: Bahari-Javan
authors.forename: Stefan
authors.initials: S
authors.lastname: Irniger
authors.forename: Kim
authors.initials: K
authors.lastname: Nasmyth
authors.forename: Farahnaz
authors.initials: F
authors.lastname: Sananbenesi
authors.forename: Andre
authors.initials: A
authors.lastname: Fischer
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D064190:Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome; D001921:Brain / Q000166:cytology; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics; D003214:Conditioning, Classical / Q000502:physiology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005108:Extinction, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology; D006801:Humans; D007859:Learning Disabilities / Q000209:etiology / Q000235:genetics; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; D012333:RNA, Messenger; D043743:Ubiquitin-Protein Ligase Complexes; C577341:Anapc2 protein, mouse; D064173:Anaphase-Promoting Complex-Cyclosome; D064190:Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C517700:Camkk2 protein, mouse