Signaling Mechanisms Underlying Reversible, Activity-Dependent Dendrite Formation

Abstract

Neuronal activity and neurotrophins play a central role in the formation, maintenance, and plasticity of dendritic arbors. Here, we show that neuronal activity, mediated by electrical stimulation, KCl depolarization, or cholinergic receptor activation, promotes reversible dendrite formation in sympathetic neurons and that this effect is enhanced by NGF. Activity-dependent dendrite formation is accompanied by increased association of HMW MAP2 with microtubules and increased microtubule stability. Inhibition of either CaMKII or the MEK-ERK pathway, both of which phosphorylate MAP2, inhibits dendrite formation, but inhibition of both pathways simultaneously is required for dendrites to retract. These data indicate that neuronal activity signals via CamKII and the ERKs to regulate MAP2:microtubule interactions and hence reversible dendrite stability, and to provide a mechanism whereby activity and neurotrophins converge intracellularly to dynamically regulate dendritic morphology.

Effects of chronic network hyperexcitability on the growth of hippocampal dendrites

“…Activation of NMDA receptors has been shown to result in activation of CREB by phosphorylation at Ser 133 (Hardingham et al, 2002;Wayman et al, 2006). Numerous upstream signaling cascades can impinge on CREB to influence gene expression and dendrite growth (Wu and Cline, 1998;Wu et al, 2001;Redmond et al, 2002;Vaillant et al, 2002;Wayman et al, 2006). Our studies suggest that following chronic bicuculline treatment the level of pCREB in hippocampal neurons is decreased while the levels of CREB itself remain unaltered.…”

“…A number of signaling cascades including the CAM Kinase and MAP Kinase cascades appear to converge on CREB to mediate their effects (Redmond et al, 2002;Vaillant et al, 2002;Wayman et al, 2006). Since our results suggest that dendritic growth is greatly diminshed by chronic disinhibition we next examined the effects of this treatment on activation of CREB by examining alterations in the phosphorylation at Ser-133.…”

“…We also show for the first time, that epileptiform activity prevents normal dendrite growth and that this is an NMDA dependent process. Moreover, a number of laboratories have recently examined the molecular mechanisms that underlie activity-dependent growth of dendrites (Redmond et al, 2002;Vaillant et al, 2002;Yu and Malenka, 2003; Van and Cline, 2004;Wayman et al, 2006). Numerous signaling cascades have been implicated in these processes.…”

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

“…To further explore the mechanism underlying the improvement in memory function and spine formation, we analyzed the levels of phosphorylation of calcium/calmodulin-dependent protein kinase II (pCaMKII; Thr286) and of extracellular signal-related kinase 1/2 (pERK1/2) that may also promote synaptic plasticity (Giese and Mizuno, 2013;Lucchesi et al, 2011;Vaillant et al, 2002). A significant increase was observed in the case of pCaMKII levels with no effects on pERK1/2 in the group of mice treated with CM-414 (Figure 4f).…”

Rapid regulation of microtubule-associated protein 2 in dendrites of nucleus laminaris of the chick following deprivation of afferent activity

“…This idea is supported by dynamic regulation of MAP2 expression and its involvement in dynamic changes in neuronal morphology caused by excitotoxins (Siman and Noszek, 1988;Bigot et al, 1991;Felipo et al, 1993;Arias et al, 1997;Faddis et al, 1997;Hoskison and Shuttleworth, 2006;Hoskison et al, 2007), traumatic brain injury (Taft et al, 1992;Folkerts et al, 1998), or focal ischemia (Pettigrew et al, 1996;Schwab et al, 1998). In addition, manipulations of synaptic activity alter the immunoreactivity for MAP2 in dendrites (Hendry and Bhandari, 1992;Steward and Halpain, 1999;Vaillant et al, 2002), further suggesting that synaptic activity either directly or indirectly regulates MAP2 expression. …”