Autocrine Action of BDNF on Dendrite Development of Adult-Born Hippocampal Neurons

Abstract

Dendrite development of newborn granule cells (GCs) in the dentate gyrus of adult hippocampus is critical for their incorporation into existing hippocampal circuits, but the cellular mechanisms regulating their dendrite development remains largely unclear. In this study, we examined the function of brain-derived neurotrophic factor (BDNF), which is expressed in adult-born GCs, in regulating their dendrite morphogenesis. Using retrovirus-mediated gene transfection, we found that deletion and overexpression of BDNF in adult-born GCs resulted in the reduction and elevation of dendrite growth, respectively. This effect was mainly due to the autocrine rather than paracrine action of BDNF, because deletion of BDNF only in the newborn GCs resulted in dendrite abnormality of these neurons to a similar extent as that observed in conditional knockout (cKO) mice with BDNF deleted in the entire forebrain. Furthermore, selective expression of BDNF in adult-born GCs in BDNF cKO mice fully restored normal dendrite development. The BDNF autocrine action was also required for the development of normal density of spines and normal percentage of spines containing the postsynaptic marker PSD-95, suggesting autocrine BDNF regulation of synaptogenesis. Furthermore, increased dendrite growth of adult-born GCs caused by voluntary exercise was abolished by BDNF deletion specifically in these neurons and elevated dendrite growth due to BDNF overexpression in these neurons was prevented by reducing neuronal activity with coexpression of inward rectifier potassium channels, consistent with activitydependent autocrine BDNF secretion. Therefore, BDNF expressed in adult-born GCs plays a critical role in dendrite development by acting as an autocrine factor.

Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons

“…This deficiency could be repaired by supplying an additional source of BDNF (or TrkB agonist) that activates WT-like TrkB signaling. BDNF has been suggested to act as an autocrine factor mainly in regulating dendrite development in adult-born granule cells (GCs) (Wang et al, 2015) and promoting axon formation in embryonic hippocampal neurons (Cheng et al, 2011). In RTT pathophysiology in particular, we show for the first time that this localized autocrine function and cell autonomy of BDNF-TrkB together offer a plausible mechanism and explain why MeCP2 mosaicism in RTT females is ineffective in restoring phenotypes at a cellular, network or behavioral level.…”

“…Similarly, endogenous MeCP2 knockdown reduced dendritic length in E18 hippocampal neurons, which was fully rescued upon BDNF overexpression (Larimore et al, 2009). Considering that BDNF is an important regulator of neurite outgrowth and synapse formation (Cheng et al, 2011; Finsterwald et al, 2010; Gottmann et al, 2009; McAllister et al, 1999; Park and Poo, 2013; Poo, 2001; Tolwani et al, 2002; Wang et al, 2015), it is essential to understand effects of BDNF modulation in Mecp2 Null/y neurons specifically in steering neuronal growth and glutamatergic synapses. Early work has focused mainly on phenotypic rescue upon increasing BDNF levels in MeCP2-deficient mice but mechanistic interactions have not been resolved.…”

Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease

“…BDNF regulates the formation and maintenance of neuronal networks associated with psychiatric disorders (Autry and Monteggia, 2012; Martinowich et al, 2007). BDNF provides trophic support and increases in synaptogenesis and dendritic and axonal branching (Nagahara et al, 2013, 2009; Park and Poo, 2013; Wang et al, 2015). Because neurotrophin signaling is germane for many neurodegenerative and psychiatric disorders where structural plasticity is compromised (Lu et al, 2013), one approach is to increase the levels of neurotrophins or signaling through its Trk receptors.…”

Kalirin is required for BDNF-TrkB stimulated neurite outgrowth and branching

“…BDNF promotes dendritic arbor growth (Ozdinler and Macklis, 2006; Reichardt, 2006; Wang et al, 2015) and axonal branching (Panagiotaki et al, 2010) by binding to TrkB (Bramham, 2008; Park and Poo, 2013), a receptor tyrosine kinase (Cohen-Cory and Fraser, 1995; McAllister et al, 1999). The binding of BDNF stimulates trans-phosphorylation of multiple Tyr residues, which triggers multiple downstream pathways, including activation of the small Rho family GTPase, Rac1 (Huang and Reichardt, 2003; Minichiello, 2009).…”