A pivotal event in the developing nervous system is formation of proper synaptic connections, a process governed by intrinsic cellular guidance cues and by extrinsic, """"""""activity-dependent"""""""", information obtained from the environment. External stimuli have their greatest impact during critical periods in which connections between nerve cells are highly plastic and susceptible to modification. At the molecular level, two of the key regulators of activity-dependence are the NMDA subtype of glutamate receptor, and brain-derived neurotrophic factor (BDNF). With the use of selective antagonists, each has been shown independently to affect the ability of growing nerve fibers to compete for postsynaptic targets and even influence the duration of critical periods during development. The central goal of this proposal is to elucidate interactions between these two molecules, thus providing insights into how they work together to refine synaptic connectivity into early adulthood.To accomplish this task, we will build upon previous work from my laboratory showing that BDNF can modify the activity of NMDA receptors in hippocampal neurons, particularly those containing the NR2B subunit. Expression levels of NR2B are highly correlated with critical period duration, and may play an obligatory role in synaptic plasticity during ontogeny. Therefore, we will determine whether BDNF modulation of NMDA receptors is prominent during early development, whether it targets synaptic or extrasynaptic NR2B-containing NMDA receptors, and whether it is hippocampus-specific or found in other brain regions as well. We will also capitalize on our new finding that modulation of NMDA receptors by BNDF is activity-dependent, an essential requirement for involvement in synaptic competition. We will use this information to determine whether BDNF modulation is synapse- or cell-specific, whether it involves neuronal release of BDNF, and whether, like many forms of synaptic plasticity, it is triggered by calcium influx through NMDA receptors.Addressing these questions will increase our knowledge of how neural circuits are constructed during development, and perhaps even help us determine how to rebuild these pathways after brain trauma.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
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Mamounas, Laura
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Rutgers University
Schools of Arts and Sciences
New Brunswick
United States
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Toyo-oka, Kazuhito; Wachi, Tomoka; Hunt, Robert F et al. (2014) 14-3-3? and ? regulate neurogenesis and differentiation of neuronal progenitor cells in the developing brain. J Neurosci 34:12168-81
Bi, Caixia; Yue, Xin; Zhou, Renping et al. (2011) EphA activation overrides the presynaptic actions of BDNF. J Neurophysiol 105:2364-74
Pramparo, Tiziano; Libiger, Ondrej; Jain, Sonia et al. (2011) Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects. PLoS Genet 7:e1001331
Pramparo, Tiziano; Youn, Yong Ha; Yingling, Jessica et al. (2010) Novel embryonic neuronal migration and proliferation defects in Dcx mutant mice are exacerbated by Lis1 reduction. J Neurosci 30:3002-12
Hippenmeyer, Simon; Youn, Yong Ha; Moon, Hyang Mi et al. (2010) Genetic mosaic dissection of Lis1 and Ndel1 in neuronal migration. Neuron 68:695-709
Youn, Yong Ha; Pramparo, Tiziano; Hirotsune, Shinji et al. (2009) Distinct dose-dependent cortical neuronal migration and neurite extension defects in Lis1 and Ndel1 mutant mice. J Neurosci 29:15520-30
Crozier, Robert A; Bi, Caixia; Han, Yu R et al. (2008) BDNF modulation of NMDA receptors is activity dependent. J Neurophysiol 100:3264-74
Yingling, Jessica; Youn, Yong Ha; Darling, Dawn et al. (2008) Neuroepithelial stem cell proliferation requires LIS1 for precise spindle orientation and symmetric division. Cell 132:474-86
Liu, Aixiao; Han, Yu R; Li, Jiadong et al. (2007) The glial or neuronal fate choice of oligodendrocyte progenitors is modulated by their ability to acquire an epigenetic memory. J Neurosci 27:7339-43
Cortes, Rosa Y; Arevalo, Juan Carlos; Magby, Jason P et al. (2007) Developmental and activity-dependent regulation of ARMS/Kidins220 in cultured rat hippocampal neurons. Dev Neurobiol 67:1687-98

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