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J Neurosci. 2015 Apr 15;35(15):6165-78. doi: 10.1523/JNEUROSCI.3013-14.2015.

Loss of F-box only protein 2 (Fbxo2) disrupts levels and localization of select NMDA receptor subunits, and promotes aberrant synaptic connectivity.

Author information

Department of Neurology.
Molecular and Behavioral Neuroscience Institute, and.
Department of Pharmacology, University of California, Davis, California 95615, Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, and.
Department of Otolaryngology, Indiana University, Indiana 46202.
Department of Pharmacology, University of California, Davis, California 95615.
Molecular and Behavioral Neuroscience Institute, and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109.
Department of Neurology,


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.


Fbxo2; GluN1; GluN2A; NMDA; synapse

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