title: A dual role for the RhoGEF Ephexin5 in regulation of dendritic spine outgrowth.
abstract: The outgrowth of new dendritic spines is closely linked to the formation of new synapses, and is thought to be a vital component of the experience-dependent circuit plasticity that supports learning. Here, we examined the role of the RhoGEF Ephexin5 in driving activity-dependent spine outgrowth. We found that reducing Ephexin5 levels increased spine outgrowth, and increasing Ephexin5 levels decreased spine outgrowth in a GEF-dependent manner, suggesting that Ephexin5 acts as an inhibitor of spine outgrowth. Notably, we found that increased neural activity led to a proteasome-dependent reduction in the levels of Ephexin5 in neuronal dendrites, which could facilitate the enhanced spine outgrowth observed following increased neural activity. Surprisingly, we also found that Ephexin5-GFP levels were elevated on the dendrite at sites of future new spines, prior to new spine outgrowth. Moreover, lowering neuronal Ephexin5 levels inhibited new spine outgrowth in response to both global increases in neural activity and local glutamatergic stimulation of the dendrite, suggesting that Ephexin5 is necessary for activity-dependent spine outgrowth. Our data support a model in which Ephexin5 serves a dual role in spinogenesis, acting both as a brake on overall spine outgrowth and as a necessary component in the site-specific formation of new spines.
authors.affiliation: Center for Neuroscience, University of California Davis, Davis, CA 95618, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Hamilton
authors.affiliation: Center for Neuroscience, University of California Davis, Davis, CA 95618, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Lambert
authors.affiliation: Center for Neuroscience, University of California Davis, Davis, CA 95618, USA.
authors.forename: L K
authors.initials: LK
authors.lastname: Parajuli
authors.affiliation: Center for Neuroscience, University of California Davis, Davis, CA 95618, USA.
authors.forename: O
authors.initials: O
authors.lastname: Vivas
authors.affiliation: Center for Neuroscience, University of California Davis, Davis, CA 95618, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Park
authors.affiliation: Center for Neuroscience, University of California Davis, Davis, CA 95618, USA.
authors.forename: I S
authors.initials: IS
authors.lastname: Stein
authors.affiliation: Center for Neuroscience, University of California Davis, Davis, CA 95618, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Jahncke
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Greenberg
authors.affiliation: Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Margolis
authors.affiliation: Center for Neuroscience, University of California Davis, Davis, CA 95618, USA. Electronic address: kzito@ucdavis.edu.
authors.forename: K
authors.initials: K
authors.lastname: Zito
mesh_terms: D000818:Animals; D049229:Dendritic Spines / Q000235:genetics* / Q000502:physiology; D018846:Excitatory Amino Acids / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000145:classification*; D009924:Organ Culture Techniques; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics*
chemical_list: D018846:Excitatory Amino Acids; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid
keywords: Activity-dependent; Dendritic spine; Ephexin5; Hippocampus; Proteasome; Structural plasticity