title: Loss of F-box only protein 2 (Fbxo2) disrupts levels and localization of select NMDA receptor subunits, and promotes aberrant synaptic connectivity.
abstract: NMDA receptors (NMDARs) play an essential role in some forms of synaptic plasticity, learning, and memory. Therefore, these receptors are highly regulated with respect to their localization, activation, and abundance both within and on the surface of mammalian neurons. Fundamental questions remain, however, regarding how this complex regulation is achieved. Using cell-based models and F-box Only Protein 2 (Fbxo2) knock-out mice, we found that the ubiquitin ligase substrate adaptor protein Fbxo2, previously reported to facilitate the degradation of the NMDAR subunit GluN1 in vitro, also functions to regulate GluN1 and GluN2A subunit levels in the adult mouse brain. In contrast, GluN2B subunit levels are not affected by the loss of Fbxo2. The loss of Fbxo2 results in greater surface localization of GluN1 and GluN2A, together with increases in the synaptic markers PSD-95 and Vglut1. These synaptic changes do not manifest as neurophysiological differences or alterations in dendritic spine density in Fbxo2 knock-out mice, but result instead in increased axo-dendritic shaft synapses. Together, these findings suggest that Fbxo2 controls the abundance and localization of specific NMDAR subunits in the brain and may influence synapse formation and maintenance.
authors: Department of Neurology.
authors: Graham
authors: G
authors: Atkin
authors: Molecular and Behavioral Neuroscience Institute, and.
authors: Shannon
authors: S
authors: Moore
authors: Department of Pharmacology, University of California, Davis, California 95615, Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, and.
authors: Yuan
authors: Y
authors: Lu
authors: Department of Otolaryngology, Indiana University, Indiana 46202.
authors: Rick F
authors: RF
authors: Nelson
authors: Department of Neurology.
authors: Nathan
authors: N
authors: Tipper
authors: Department of Neurology.
authors: Gautam
authors: G
authors: Rajpal
authors: Department of Neurology.
authors: Jack
authors: J
authors: Hunt
authors: Department of Neurology.
authors: William
authors: W
authors: Tennant
authors: Department of Pharmacology, University of California, Davis, California 95615.
authors: Johannes W
authors: http://orcid.org/0000-0001-7960-7531
authors: JW
authors: Hell
authors: Molecular and Behavioral Neuroscience Institute, and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109.
authors: Geoffrey G
authors: GG
authors: Murphy
authors: Department of Neurology, henryp@umich.edu.
authors: Henry
authors: H
authors: Paulson
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D021381:Protein Transport / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D013574:Synaptosomes / Q000378:metabolism / Q000648:ultrastructure; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018691:Excitatory Amino Acid Antagonists; D044783:F-Box Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D050598:Vesicular Glutamate Transport Protein 1; C121673:Gprin1 protein, mouse; C493465:Slc17a7 protein, mouse
keywords: Fbxo2; GluN1; GluN2A; NMDA; synapse