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.

Adolescent pruning and stabilization of dendritic spines on cortical layer 5 pyramidal neurons do not depend on gonadal hormones

“…If hormones do not play a role in the pruning and stabilization of dendritic spines on layer 5 neurons, then what factors drive these processes? Age, neural activity, and stress hormones can be linked to changes in intracellular proteins ( Gray et al, 2006 ; Hamilton et al, 2017 ; Liston et al, 2013 ) and cell–cell adhesion molecules ( Kwon et al, 2012 ) that may play a regulatory role in spine maturation. Experience itself (or the lack of experience) may also drive the stabilization of synapses and serve to regulate plasticity ( Johnson et al, 2016b ; Panchanathan and Frankenhuis, 2016 ; Roberts et al, 2010 ; Wilbrecht et al, 2010 ; Wilbrecht et al, 2006 ; Zuo et al, 2005b ).…”

HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory

“…Although a more in depth analysis of mitochondrial dynamics is needed in tbl neurons, the possibility exists that alterations to the interactions between Rab proteins and mutated HERC1 could alter late endosome-mitochondrial relationships; inducing mitochondrial dysfunction and eliciting the anomalous mitophagy that disrupts neuronal homeostasis (Martinez-Vicente, 2017). The E3 ligases in the UPS have been implicated in the maintenance of spine size, density and number, through regulation of AMPA receptor expression, or of NMDA receptor and RhoA activity (Hamilton and Zito, 2013;Mertz et al, 2015;Hamilton et al, 2017). Indeed, spinogenesis is also dampened when UPS activity is blocked (Hamilton and Zito, 2013).…”

Emerging Roles of Ephexins in Physiology and Disease

“…Interestingly, the complete loss of Ephexin5 prevents neuronal activity from promoting spinogenesis. Taken together, these data indicate that Ephexin5 may serve as a beacon locating sites of new spine formation keeping them in check until incoming activity promotes spine formation at these sites [74].…”