Impaired dendritic development and synaptic formation of postnatal-born dentate gyrus granular neurons in the absence of brain-derived neurotrophic factor signaling

Abstract

Neurons are continuously added to the hippocampal dentate gyrus throughout life. These neurons must develop dendritic arbors and spines by which they form synapses for making functional connections with existing neurons. The molecular mechanisms that regulate dendritic development and synaptic formation of postnatal-born granular neurons in the dentate gyrus are largely unknown. Hippocampal dentate gyrus (HDG) has been shown to express high level of brain-derived neurotrophic factor (BDNF). Here we reported that when BDNF is conditionally knockout in the postnatal-born granular neurons of the HDG, the mutant neurons exhibit aberrant morphological development with less dendritic branches, shorter dendritic length, and lower density of dendritic spines, while their primary dendrites are not obviously affected. Even though, these BDNF-deficient granular neurons develop immature dendritic spines to initiate synaptic contacts with afferent axons, they fail to develop or maintain mature spine structures. Thus, these postnatal-born neurons have fewer numbers of synapses, particularly mature synaptic spines. These results suggest that BDNF plays an important role during dendritic development, synaptic formation and synaptic maturation in postnatal-born granular neurons of the HDG in vivo.

Introduction

Neurogenesis, the birth of new neurons, occurs throughout adulthood in certain regions of the mammalian brain. Specifically, neurons are continuously generated from neural progenitor cells (NPCs) in the subgranular zone (SGZ) of the HDG (Eriksson et al., 1998, Gage, 2002, Kempermann et al., 2006, Kempermann et al., 2004, Taupin and Gage, 2002, van Praag et al., 2002) and in the subventricular zone (SVZ) of the frontal cortex (Alvarez-Buylla, 1997, Alvarez-Buylla and Garcia-Verdugo, 2002, Doetsch et al., 1999). These adult-born neurons are electrically active and capable of firing action potentials or receiving synaptic inputs (Carlen et al., 2002, Markakis and Gage, 1999, van Praag et al., 2002), suggesting that they are adequately integrated into existing neural circuitry. The finding that neurogenesis occurs in the adult mammalian CNS suggests promising therapeutic possibilities for treating CNS disease or injury, such as repairing CNS damage by NPC transplantation (Emsley et al., 2005, Taupin, 2005) or by inducing neurogenesis from endogenous NPCs (Chen et al., 2004, Magavi et al., 2000). In order to integrate into the existing neural network or rebuild neural circuitry, these newborn neurons must develop dendrites and dendritic spines to form connections with existing neurons to receive and convey information. However, the molecular mechanisms that underlie this process remain a fascinating puzzle.

The main input apparatus of a neuron is the dendrite, which bears most of the neuronal synapses. Dendritic morphogenesis including the development of primary dendrites, dendritic branches, and dendritic spines, allows neurons to communicate with each other, and therefore is one of the critical steps in the process of neurogenesis. Dendritic morphogenesis has been widely studied during early neural development. Investigations of cortical dendrite development revealed that extracellular signals exert considerable influence over the specification of dendritic morphology. The emergence and growth of primary dendrites are regulated by a number of factors, including neurotrophins, Notch1, and Slit1 (McAllister et al., 1995, Redmond and Ghosh, 2001, Redmond et al., 2000, Salama-Cohen et al., 2005, Whitford et al., 2002). Of these, the effects of neurotrophins have been examined most extensively. In particular, BDNF has been reported to regulate primary dendrite formation (Dijkhuizen and Ghosh, 2005) and play an important role in regulating the growth and branching of cortical dendrites (McAllister et al., 1995, Niblock et al., 2000). Overexpression of either BDNF (Horch et al., 1999) or its high affinity receptor, TrkB, (Yacoubian and Lo, 2000) favors addition of dendritic branches close to the soma. BDNF also appears to regulate the dynamic stability of dendritic processes (Horch, 2004, Horch and Katz, 2002, Horch et al., 1999). Most of these signals have been studied with regard to their effects on dendrite extension and branching during early development. The molecular mechanisms that regulate dendritic development and synaptic formation of postnatal-born granular neurons in the dentate gyrus are largely unknown. In this study, we examine the role of BDNF in dendritogenesis and synaptogenesis in postnatal-born neurons. When we conditionally knocked out BDNF in newborn neurons of the postnatal dentate gyrus, we observed a dramatic defect in dendritic arborization and spine formation, suggesting that this protein is involved in dendritic development, and spine formation in postnatal-born neurons in vivo.