PDF《REVIEW ARTICLE》

REVIEW ARTICLE published:

20 August

2013 doi: 10.

3389/fnsyn.2013.00004 Maturation and integration of adult born hippocampal neurons: signal convergence onto small Rho GTPases Krishna C. Vadodaria1,2? and Sebastian Jessberger1,2 *

1 2 Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland Edited by: Akira Yoshii, McGovern Institute for Brain Research at Massachusetts Institute of Technology, USA Reviewed by: Linda Van Aelst, Cold Spring Harbor Laboratory, USA Ayumu Tashiro, Nanyang Technological University, Singapore *Correspondence: Adult neurogenesis, restricted to speci?c regions in the mammalian brain, represents one of the most interesting forms of plasticity in the mature nervous system. Adult-born hippocampal neurons play important roles in certain forms of learning and memory, and altered hippocampal neurogenesis has been associated with a number of neuropsychiatric diseases such as major depression and epilepsy. Newborn neurons go through distinct developmental steps, from a dividing neurogenic precursor to a synaptically integrated mature neuron. Previous studies have uncovered several molecular signaling pathways involved in distinct steps of this maturational process. In this context, the small Rho GTPases, Cdc42, Rac1, and RhoA have recently been shown to regulate the morphological and synaptic maturation of adult-born dentate granule cells in vivo. Distinct upstream regulators, including growth factors that modulate maturation and integration of newborn neurons have been shown to also recruit the small Rho GTPases. Here we review recent ?ndings and highlight the possibility that small Rho GTPases may act as central assimilators, downstream of critical input onto adult-born hippocampal neurons contributing to their maturation and integration into the existing dentate gyrus (DG) circuitry. Keywords: neurogenesis, Rac1, Cdc42, RhoA, synaptic integration, spine growth, dendrite, in vivo INTRODUCTION Throughout lifespan new neurons are continuously born in the mammalian hippocampus. It is now widely accepted that the process of adult neurogenesis is not merely a remnant of embry- onic development, but a highly responsive and regulated process that appears to be critically involved in hippocampus-dependent behavior in health and disease (Sahay and Hen, 2007;

Zhao et al., 2008;

Danzer, 2012). The number of newborn neurons in the adult hippocampus is not static but strongly in?uenced by many positive and negative stimuli that in?uence the neuro- genic process at distinct developmental stages. Positive extrinsic regulators include physical exercise, environmental enrichment, antidepressants, and learning, whereas stress and aging nega- tively regulate the number of newly generated neurons (Ma et al., 2009). These stimuli are thought to impact adult neurogenesis via a number of regulatory pathways including growth factors, neurotransmitters, developmental signaling molecules, and hor- mones. Inspired by previous studies in the context of embryonic neurogenesis, a number of cellular and molecular mechanisms, involved in the control of neural stem/progenitor cells (NSPC) activity and subsequent integration of newborn granule cells within the adult hippocampus, have been identi?ed (Ming and Song, 2011). Even though it has been demonstrated that the neurogenic process in the adult hippocampus shares many prop- erties with embryonic neurogenesis, it principally differs from embryonic neurogenesis in that, NSPCs and maturing neurons are present in an entirely different (adult) environment and must integrate into a preexisting circuit, presumably in the absence of large amounts of developmental guidance cues (Conover and Notti, 2008). Thus, understanding the molecular underpinnings of how adult-born neurons integrate into the dentate gyrus (DG) circuitry requires experiments that analyze the cellular mechanisms and signaling pathways in their endogenous adult niche. Recently, a few reports demonstrate stage-speci?c roles for small Rho GTPases, Cdc42, Rac1, and RhoA in adult hippocam- pal neurogenesis in vivo. These studies suggest an important and potentially central role for the small Rho GTPases in the maturation and integration of newborn neurons in the adult hippocampus. In this mini-review, we discuss the main ?nd- ings of recent in vivo studies and then focus on discussing how known upstream intrinsic regulators (neurotrophins, neurotrans- mitters, developmental signaling molecules, and intermediate signaling molecules) maybe recruiting Rho GTPases for mediat- ing their effects on neuronal maturation in adulthood. We begin by describing the maturation process of adult born hippocam- pal neurons and give a broad overview of neuronal Rho GTPase signaling, followed by a discussion of evidence showing how important regulators of neuronal maturation may be modulat- ing small Rho GTPases as downstream effectors. We conclude with hypotheses on mechanisms for signal convergence and a brief discussion of how Rho GTPases may act to assimilate multi- ple upstream signals to decisively in?uence cell cytoskeleton and neuronal cytoarchitecture. For a more detailed discussion on Rho GTPase signaling in neurons, please refer to other reviews (Auer et al., 2011;