Taurine Induces Proliferation of Neural Stem Cells and Synapse Development in the Developing Mouse Brain Mattu Chetana Shivaraj1, Guillaume Marcy1, Guoliang Low1, Jae Ryun Ryu1, Xianfeng Zhao2, Francisco J. Rosales2, Eyleen L. K. Goh1,3,4* 1 Program in Neuroscience and Behavioral Disorder, Duke-NUS Graduate Medical School, Singapore, Singapore, 2 Cognition Center of Excellence, Abbott Nutrition Research & Development, Asia Pacific Center, Singapore, Singapore, 3 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore, 4 A*STAR-Duke-NUS Neuroscience Research Partnership, Proteos, Singapore, Singapore Abstract Taurine is a sulfur-containing amino acid present in high concentrations in mammalian tissues. It has been implicated in several processes involving brain development and neurotransmission. However, the role of taurine in hippocampal neurogenesis during brain development is still unknown. Here we show that taurine regulates neural progenitor cell (NPC) proliferation in the dentate gyrus of the developing brain as well as in cultured early postnatal (P5) hippocampal progenitor cells and hippocampal slices derived from P5 mice brains. Taurine increased cell proliferation without having a significant effect on neural differentiation both in cultured P5 NPCs as well as cultured hippocampal slices and in vivo. Expression level analysis of synaptic proteins revealed that taurine increases the expression of Synapsin 1 and PSD 95. We also found that taurine stimulates the phosphorylation of ERK1/2 indicating a possible role of the ERK pathway in mediating the changes that we observed, especially in proliferation. Taken together, our results demonstrate a role for taurine in neural stem/ progenitor cell proliferation in developing brain and suggest the involvement of the ERK1/2 pathways in mediating these actions. Our study also shows that taurine influences the levels of proteins associated with synapse development. This is the first evidence showing the effect of taurine on early postnatal neuronal development using a combination of in vitro, ex-vivo and in vivo systems. Citation: Shivaraj MC, Marcy G, Low G, Ryu JR, Zhao X, et al. (2012) Taurine Induces Proliferation of Neural Stem Cells and Synapse Development in the Developing Mouse Brain. PLoS ONE 7(8): e42935. doi:10.1371/journal.pone.0042935 Editor: Xin-Yun Lu, University of Texas Health Science Center at San Antonio, United States of America Received January 5, 2012; Accepted July 15, 2012; Published August 20, 2012 Copyright: 2012 Shivaraj et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The present research is supported by: A Startup fund from Duke-NUS Graduate Medical School, Singapore 169857 and Abbott Nutrition Research & Development, Singapore 138668. The funders had no role in study design, data collection, decision to publish and analysis or preparation of the manuscript. Competing Interests: The authors have read the journal’s policy and have the following conflicts: EG is consultant for and FR and XZ are employees of Abbott Nutrition Research & Development. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors. * E-mail: eyleen.goh@duke-nus.edu.sg Introduction The development of the nervous system involves the coordina- tion of specific cellular events including proliferation, differentia- tion, migration, outgrowth of axons and dendrites, formation of synapses, myelination, and programmed cell death. Chemical- mediated disruption of one or more of these processes can potentially disrupt the function of the nervous system [1,2]. Synaptic plasticity has also been known to be closely associated with neural system development [3] and has been defined as the modification of synapses structurally and functionally by different stimuli and environmental cues such as activity and intrinsic determinant [4]. The hippocampus plays important roles in long- term and spatial memory, storage, retrieval and navigation [5]. Newly generated neural precursor cells from the sub-granular proliferative zone at the DG migrate to regions of differentiation, where they grow, develop and become matured neurons [6,7]. In becoming matured, functionally integrated neurons, the newborn cells must first acquire the ability to form dendrites and synapses, to receive synaptic contacts and to extend axons, processes [6,8] that are influenced by many factors. Compound absorbed through the diet have long been touted to affect postnatal neural development and neurogenesis [9]. A study showed that a food product derivative, apigenin stimulates neurogenesis in the mice hippocampus by promoting neuronal differentiation, and also enhanced learning and memory [10]. Neuroactive compounds such as cocaine and cannabinoids were also shown to alter the proliferation and differentiation rates of NPCs and result in subsequent neurodevelopment and neurocognitive deficits [11,12]. Taurine (2-aminoethanesulfonic acid) plays an important role in several essential biological processes such as development of the central nervous system and the retina, reproduction, immune- modulation, osmoregulation, and membrane stabilization [13,14,15]. Endogenous taurine is derived from cysteine. The brain synthesizes only a limited amount of taurine, and most taurine synthesis occurs in the liver [16]. Taurine is suggested to have an important role in brain development, as its level is 3–4 times higher in developing and neonatal brain than adult brain [17]. This age related decline is a consistent feature observed among species, regardless of their original differences in taurine concentration [18]. Studies in monkeys fed with dietary formulas without taurine showed prominently a defective organization of cortical layers in the visual cortex [15]. Cats born from taurine deficient mothers have smaller brain weight and an abnormal morphology in the cerebellum and the visual cortex. Delayed migration of neuroblasts and glioblasts is also observed in the PLOS ONE | www.plosone.org 1 August 2012 | Volume 7 | Issue 8 | e42935