Vasoactive Intestinal Peptide and PACAP38 Control N-Methyl-D-aspartic Acid-induced Dendrite Motility by Modifying the Activities of Rho GTPases and Phosphatidylinositol 3-Kinases

Abstract

Dendrite morphogenesis is highly dynamic and characterized by the addition and elongation of processes and also by their selective maintenance, retraction, and elimination. Glutamate can influence these events via N-methyl-D-aspartic acid (NMDA) receptors. The neuropeptides vasoactive intestinal peptide and pituitary adenylyl cyclase-activating polypeptide-38 (PACAP38) affect neurogenesis and differentiation in the developing nervous system. We report here that the peptides and NMDA acted synergistically on dendrite and branch formation. In stage III hippocampal neurons, NMDA increased not only the addition but also the elimination of new dendrites and branches by activating Rac and Cdc42 and phosphatidylinositol 3-kinases, respectively. When applied alone, the neuropeptides did not influence dendrite or branch formation. However, they reduced the elimination of newly formed dendrites and branches caused by NMDA by preventing the NMDA-induced activation of phosphatidylinositol 3-kinases. This led to the formation of persistent dendrites and branches. Additional timelapse studies on the dynamics of dendrite elongation showed alternating periods of elongation and retraction. Phosphatidylinositol 3-kinases increased the velocities of dendrite elongation and retraction, whereas the neuropeptides prolonged the periods of elongation. By modifying NMDA-induced activation of Rho GTPases and phosphatidylinositol 3-kinases, vasoactive intestinal peptide and PACAP38 could play an important role in the control of dendrite growth and branching during development and in response to neuronal activity.To integrate synaptic input, neurons develop a specific dendritic branching pattern that determines their function (1). Neuronal activity modifies the formation and stabilization of dendritic processes (2, 3). Dendrites are motile structures that contain high concentrations of filamentous actin. By controlling the stability and assembly of the actin cytoskeleton, members of the Rho family of small GTPases regulate neuronal morphogenesis (4). Rac and Cdc42 facilitate the outgrowth of dendrites, dendritic branches, filopodia, and spines, whereas RhoA and Rho kinase (ROCK) 3 attenuate it (5-9). In Xenopus optic tectal neurons, the neurotransmitter glutamate changes the activity of Rho GTPases by acting on ionotropic NMDA (NMDAR) and L-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors. It facilitates dendrite formation by inhibiting RhoA and activating Rac (10). Because calcium signaling plays an important role in dendrite formation (11,12), mainly the effects of NMDAR stimulation seem to be important. In hippocampal neurons, the guanine exchange factor Tiam1 couples NMDARs to the activity-dependent development by activating Rac1 and inhibiting RhoA (13,14).In vitro, class I phosphatidylinositol 3-kinases (PI3Ks) support neurite formation by producing membrane-bound phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate (15-17). PI3Ks stimulate dendrite and branch outgrowth by inhibiting the RhoA/...

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

“…Consistent with this finding, PACAP and PAC1-R mRNA expressions are transiently increased in the cortex and the hippocampus after traumatic brain injury (Skoglösa et al, 1999a;Stumm et al, 2007). Besides its neuroprotective activity, PACAP reduces the number of damaged axons after traumatic injury (Farkas et al, 2004;Tamá s et al, 2006), favors dendrite outgrowth through the Rho PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE GTPase and PI3-K pathways in response to neuronal activity (Henle et al, 2006) and enhances NMDA receptor activity (Macdonald et al, 2005), which probably contribute to functional recovery. PACAP also exerts a neuroprotective effect against retinal degeneration induced by carotid occlusion, kainic acid, and monosodium glutamate (Babai et al, 2005(Babai et al, , 2006Seki et al, 2006b;Atlasz et al, 2007Atlasz et al, , 2008.…”

δ-Catenin-induced Dendritic Morphogenesis

“…53 (12) showed that a deletion of 99 amino acid (aa) residues from the ␦-catenin COOH-terminal (⌬C99), but not a deletion of 205 aa (⌬C205), retains its ability to interact with Cortactin. As RhoA combines with the glutamate receptors at the spine plasma membrane and NMDA receptor activation decreases the RhoA activity (55,56), the C terminus of ␦-catenin may affect the Rho activity by interacting with one or more of these newly identified proteins. It also would be interesting to examine whether Cortactin or 14-3-3 mediates ␦-catenin-dependent RhoA inactivation and dendritic spine morphogenesis.…”

Functions of Rac GTPases during Neuronal Development

“…The morphogenesis of dendrites is highly dynamic, and characterized by addition, elongation, but also maintenance and retraction of dendritic processes. In hippocampal neurons, a model system to study the establishment of neuronal polarity in vitro [Craig and Banker, 1994], NMDA-induced increased dynamics of dendrites and dendritic branches is accompanied by endogenous Rac activation and prevented by expression of N17Rac1 [Henle et al, 2006]. Rac1 has also been implicated in the regulation of growth cone collapse or expansion induced by different extracellular ligands [Jin and Strittmatter, 1997;Kuhn et al, 1999;Vastrik et al, 1999;Shekarabi et al, 2005].…”