ORIGINAL RESEARCH ARTICLE published: 30 September 2009 doi: 10.3389/neuro.22.001.2009 Synaptic network activity induces neuronal differentiation of adult hippocampal precursor cells through BDNF signaling Harish Babu1,2†, Gerardo Ramirez-Rodriguez 1‡, Klaus Fabel 3, Josef Bischofberger 4 and Gerd Kempermann1,2,3* 1 Max Delbrück Center for Molecular Medicine Berlin-Buch, Berlin, Germany 2 VolkswagenStiftung Research Group, Department of Experimental Neurology, Charité University Medicine Berlin, Berlin, Germany 3 CRTD-DFG Research Center for RegenerativeTherapies Dresden, Dresden, Germany 4 Physiological Institute, University of Freiburg, Freiburg, Germany Edited by: Jack M. Parent, University of Michigan, USA Reviewed by: J. Martin Wojtowicz, University ofToronto, Canada Linda Overstreet-Wadiche, University of Alabama at Birmingham, USA *Correspondence: Gerd Kempermann, CRTD-DFG Research Center for Regenerative Therapies Dresden,Tatzberg 47–49, 01307 Dresden, Germany. e-mail: gerd.kempermann @crt-dresden.de †Present address: Harish Babu, Department of Neurosurgery, Stanford University, Stanford, CA, USA. ‡Present address: Gerardo Ramirez- Rodriguez, National Institute of Psychiatry “Ramón de la Fuente Muñiz”, Neuropharmacology Department, México, México. Adult hippocampal neurogenesis is regulated by activity. But how do neural precursor cells in the hippocampus respond to surrounding network activity and translate increased neural activity into a developmental program? Here we show that long-term potentiation (LTP)-like synaptic activity within a cellular network of mature hippocampal neurons promotes neuronal differentiation of newly generated cells. In co-cultures of precursor cells with primary hippocampal neurons, LTP-like synaptic plasticity induced by addition of glycine in Mg2+-free media for 5 min, produced synchronous network activity and subsequently increased synaptic strength between neurons. Furthermore, this synchronous network activity led to a signiﬁcant increase in neuronal differentiation from the co-cultured neural precursor cells. When applied directly to precursor cells, glycine- and Mg2+-free solution did not induce neuronal differentiation. Synaptic plasticity-induced neuronal differentiation of precursor cells was observed in the presence of GABAergic neurotransmission blockers but was dependent on NMDA-mediated Ca2+ inﬂux. Most importantly, neuronal differentiation required the release of brain-derived neurotrophic factor (BDNF) from the underlying substrate hippocampal neurons as well as TrkB receptor phosphorylation in precursor cells.This suggests that activity-dependent stem cell differentiation within the hippocampal network is mediated via synaptically evoked BDNF signaling. Keywords: hippocampus, precursor cell, adult neurogenesis, long-term potentiation, neurotrophins, network oscillation INTRODUCTION 2006; Garthe et al., 2009), which might be important for preferential Adult hippocampal neurogenesis originating from neural precursor integration of young neurons in new memory circuits (Kee et al., cells in the adult hippocampus has been linked to memory forma- 2007). The general idea, supported by several studies demonstrating tion by providing structural network optimization (Wiskott et al., the increased survival of newborn neurons in response to learning 2006; Aimone et al., 2009; Garthe et al., 2009). New neurons inte- stimuli, is that the new cells undergo a “critical period” after they grate into the existing circuitry and survive lifelong (Kempermann were born (Kempermann et al., 1997; Gould et al., 1999; Greenough et al., 2003). Neuronal activity regulates neuronal differentiation in et al., 1999; Van Praag et al., 1999b; Kee et al., 2007; Tashiro et al., the adult hippocampus via synaptic GABA and glutamate release 2007). Much less is known about the early time periods, before (Tozuka et al., 2005; Ge et al., 2007). Kainic acid, an agonist at the GABAergic and glutamatergic synaptic transmission develop (van non-NMDA receptor subtype of glutamate receptors, induces an Praag et al., 2002; Esposito et al., 2005). This raised the important increase in the number of newborn granule cells (Bengzon et al., question, how neuronal network activity might inﬂuence the earli- 1997; Parent et al., 1997). Although the proportion of active granule est stages of adult neurogenesis. We hypothesize that neural precur- cells is sparse (Chawla et al., 2005), single neurons ﬁre brief high sor cells can sense surrounding network activity and translate this frequency bursts (Axmacher et al., 2006) which might be impor- information into a pro-neurogenic signal. Could therefore coherent tant not only for induction of synaptic plasticity but – as we rea- synchronous network activity induce neuronal differentiation? soned – also for the modulation of adult neurogenesis. Behavioral activity such as voluntary physical exercise and Network oscillations are believed to be important for tempo- environmental enrichment generate synchronized activity in the ral coding, information processing and storage of new memories hippocampus and modulate learning and LTP (Van Praag et al., (Buzsaki, 2002). Theta rhythms (∼5–10 Hz) promote induction of 1999a; Duffy et al., 2001). Similarly, environmental enrichment, synaptic plasticity in mature and newborn granule cells (Schmidt- physical exercise, and learning paradigms regulate neurogenesis Hieber et al., 2004). Adult-born hippocampal neurons are highly in the dentate gyrus (DG) (Kempermann et al., 1997; Gould et al., excitable and show transiently enhanced LTP as compared to older 1999; Van Praag et al., 1999a; Leuner et al., 2004). Although both granule cells at about 2–6 weeks after cell division (Wang et al., adult neurogenesis and synaptic plasticity are considered relevant 2000a; Snyder et al., 2001; Schmidt-Hieber et al., 2004; Saxe et al., for hippocampal function, the question whether there is a link www.frontiersin.org September 2009 | Volume 3 | Article 49 | 1