A dual role for the RhoGEF Ephexin5 in regulation of dendritic spine outgrowth

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...

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Bibliographic Details
Published in:	Molecular and cellular neuroscience Vol. 80; pp. 66 - 74
Main Authors:	Hamilton, A.M., Lambert, J.T., Parajuli, L.K., Vivas, O., Park, D.K., Stein, I.S., Jahncke, J.N., Greenberg, M.E., Margolis, S.S., Zito, K.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-04-2017
Subjects:	Activity-dependent Animals Dendritic spine Dendritic Spines - genetics Dendritic Spines - physiology Ephexin5 Excitatory Amino Acids - pharmacology Female Glutamic Acid - pharmacology Green Fluorescent Proteins Hippocampus Hippocampus - cytology In Vitro Techniques Male Mice, Inbred C57BL Mice, Knockout Microscopy, Confocal Neuronal Plasticity - physiology Neurons - classification Organ Culture Techniques Proteasome Rats Rats, Sprague-Dawley Rho Guanine Nucleotide Exchange Factors - genetics Rho Guanine Nucleotide Exchange Factors - metabolism RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Structural plasticity Synapses - genetics Dendritic spine Ephexin5 Structural plasticity Activity-dependent Hippocampus Proteasome
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Summary:	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. •The RhoGEF, Ephexin5, is a negative regulator of dendritic spine outgrowth.•Neural activity drives a proteasome-dependent reduction in dendritic Ephexin5.•Ephexin5 accumulates on the dendrite prior to new spine outgrowth.•Ephexin5 is necessary for neural activity-dependent spine outgrowth.•Ephexin5 serves a dual role in spinogenesis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1044-7431 1095-9327
DOI:	10.1016/j.mcn.2017.02.001