Differential roles of Rap1 and Rap2 small GTPases in neurite retraction and synapse elimination in hippocampal spiny neurons

Georgetown University Medical School, Department of Physiology and Biophysics, Washington, DC 20057, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 02/2007; 100(1):118-31. DOI: 10.1111/j.1471-4159.2006.04195.x
Source: PubMed


The Rap family of small GTPases is implicated in the mechanisms of synaptic plasticity, particularly synaptic depression. Here we studied the role of Rap in neuronal morphogenesis and synaptic transmission in cultured neurons. Constitutively active Rap2 expressed in hippocampal pyramidal neurons caused decreased length and complexity of both axonal and dendritic branches. In addition, Rap2 caused loss of dendritic spines and spiny synapses, and an increase in filopodia-like protrusions and shaft synapses. These Rap2 morphological effects were absent in aspiny interneurons. In contrast, constitutively active Rap1 had no significant effect on axon or dendrite morphology. Dominant-negative Rap mutants increased dendrite length, indicating that endogenous Rap restrains dendritic outgrowth. The amplitude and frequency of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-mediated miniature excitatory postsynaptic currents (mEPSCs) decreased in hippocampal neurons transfected with active Rap1 or Rap2, associated with reduced surface and total levels of AMPA receptor subunit GluR2. Finally, increasing synaptic activity with GABA(A) receptor antagonists counteracted Rap2's inhibitory effect on dendrite growth, and masked the effects of Rap1 and Rap2 on AMPA-mediated mEPSCs. Rap1 and Rap2 thus have overlapping but distinct actions that potentially link the inhibition of synaptic transmission with the retraction of axons and dendrites.

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    • "In axons, for example, Nedd4 has repeatedly been shown to promote arborization via ubiquitylation of PTEN [15,18], a central inhibitor of PI3K signaling and cytoskeletal growth [33,34]. Moreover, Nedd4 is known to promote dendritic branching via ubiquitylation of Rap2 [16], a negative regulator of dendrite growth [35]. Based on the aforementioned facts, in future studies, it will be important to characterize a potential N4BP3-Nedd4 complex in neurons and analyze its impact on PTEN and Rap2 function during neurite development. "
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    ABSTRACT: Circuit formation in the nervous system essentially relies on the proper development of neurons and their processes. In this context, the ubiquitin ligase Nedd4 is a crucial modulator of axonal and dendritic branching. Herein we characterize the Nedd4-binding protein 3 (N4BP3), a Fezzin family member, during nerve cell development. In developing rat primary hippocampal neurons, endogenous N4BP3 localizes to neuronal processes, including axons and dendrites. Transient in vitro knockdown of N4BP3 in hippocampal cultures during neuritogenesis results in impaired branching of axons and dendrites. In line with these findings, in vivo knockdown of n4bp3 in Xenopus laevis embryos results in severe alteration of cranial nerve branching. We introduce N4BP3 as a novel molecular element for the correct branching of neurites in developing neurons and propose a central role for an N4BP3-Nedd4 complex in neurite branching and circuit formation.
    Neural Development 09/2013; 8(1):18. DOI:10.1186/1749-8104-8-18 · 3.45 Impact Factor
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    • "Similar decreases in ERK1/2, ERK5, MEK1, and CREB are reported in the hippocampus of suicide victims (Dwivedi et al., 2007, Dwivedi et al., 2009). Rap1, a small Ras-like GTPase, is involved in regulation of spatial memory as well as LTP, coupling cAMP signaling to p42/p44 MAPK and is known to induce removal of surface GluR2/3 containing AMPA receptors (Morozov et al., 2003, Fu et al., 2007). Similar reductions of Rap1 activity were described in PFC and hippocampus of depressed suicidal victims (Dwivedi et al., 2006). "
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    ABSTRACT: Dendritic spines provide a compartment for assembly and functional organization of synaptic machinery that plays a fundamental role in neuronal communication and neuroplasticity. Studies in humans as well as in animal models have demonstrated abnormal spine architecture in several psychiatric disorders, including depression and other stress-related illnesses. The negative impact of stress on the density and organization of spines is thought to contribute to the behavioral deficits caused by stress exposure. Moreover, there is now evidence that medication-induced recovery involves changes in synaptic plasticity and dendrite morphology, including increased expression of pre- and postsynaptic plasticity-related proteins, as well as the density and function of axo-spinous synapses. Here we review the evidence from brain imaging and postmortem studies demonstrating that depression is accompanied by structural and functional alterations of cortical and limbic brain regions, including the prefrontal cortex, hippocampus and amygdala. In addition, we present more direct evidence from basic research studies that exposure to stress alters spine morphology, function and plasticity and that antidepressants, particularly new rapid acting agents, reverse these effects. Elucidation of the signaling pathways and molecular mechanisms that control spine synapse assembly and plasticity will contribute to a better understanding of the pathophysiology of depression and development of novel, more effective therapeutic agents.
    Neuroscience 10/2012; 251. DOI:10.1016/j.neuroscience.2012.09.057 · 3.36 Impact Factor
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    • "An important difference between the two subfamilies is that Rap2 proteins typically display a lower sensitivity to GAPs, promoting a prolonged Rap2 signaling compared to that of Rap1. Although regulated by the same set of GEFs and GAPs, Rap1 and Rap2 can be involved in distinct processes, as shown in cell types different from platelets [17, 18], suggesting that they may operate through different effectors. The biochemical basis of these different effects has not been thoroughly investigated; however it might also be related to the differences in posttranslational modifications and subcellular localization of Rap1 and Rap2 isoforms [19]. "
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    ABSTRACT: Integrins and other families of cell adhesion receptors are responsible for platelet adhesion and aggregation, which are essential steps for physiological haemostasis, as well as for the development of thrombosis. The modulation of platelet adhesive properties is the result of a complex pattern of inside-out and outside-in signaling pathways, in which the members of the Rap family of small GTPases are bidirectionally involved. This paper focuses on the regulation of the main Rap GTPase expressed in circulating platelets, Rap1b, downstream of adhesion receptors, and summarizes the most recent achievements in the investigation of the function of this protein as regulator of platelet adhesion and thrombus formation.
    06/2012; 2012:412089. DOI:10.1155/2012/412089
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