proBDNF Negatively Regulates Neuronal Remodeling, Synaptic Transmission, and Synaptic Plasticity in Hippocampus

Abstract

Summary Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF which binds p75NTR. In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knock-in mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75NTR. Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission and plasticity, effects that are distinct from mature BDNF.

Lrig1 is a cell‐intrinsic modulator of hippocampal dendrite complexity and BDNF signaling

“…Axonal and dendritic morphology is regulated by both growth-promoting and growth-inhibiting factors. BDNF and NT4 are neurotrophins that promote the development and plasticity of dendritic arbors and spines through TrkB receptor signaling [4,10,51,52].…”

Pro-Brain-Derived Neurotrophic Factor Inhibits GABAergic Neurotransmission by Activating Endocytosis and Repression of GABAAReceptors

“…To investigate whether the endogenous release of proBDNF depends on the regulated secretory pathway (Haubensak et al, 1998;Zhou et al, 2004;Yang et al, 2009), we analyzed the effect of aprotinin in the presence of nifedipine (10 M), an inhibitor of L-type VGCCs, which are known to prevent dendritic release of BDNF (Kuczewski et al, 2008a). In the presence of nifedipine, aprotinin failed to decrease the expression of GABA A R ␤ 2/3 subunits at the membrane (103.1 Ϯ 2.2% compared with control, p ϭ 0.363, n ϭ 6; Fig.…”

“…To produce mature BDNF (mBDNF), proBDNF is cleaved by furin in the trans-Golgi network (Mowla et al, 2001), or by extracellular plasmin or matrixmetalloprotease-7 once secreted (Lee et al, 2001). The proteolysis of proBDNF is regulated by neuronal activity that in turn determines the extracellular ratio between mBDNF and proBDNF (Lessmann and Brigadski, 2009;Yang et al, 2009). ProBDNF and mBDNF are assumed to produce opposing physiological responses mediated by the activation of two distinct classes of transmembrane receptors, the tropomyosin-related kinase receptor B (TrkB) and the p75 neurotrophin receptor (p75 NTR ; Lee et al, 2001;.…”

Role of GPR40 for Fish Oil PUFA-mediated BDNF Synthesis in the Monkey Hippocampus

“…It has been implicated for the differentiation and survival of the CNS neurons, because of the most abundant and widespread expression not only in the developing brain but also in the adult mammalian brain [5]. Furthermore, BDNF p-BDNF and m-BDNF may have opposite biological effects; p-BDNF induces cell death whereas m-BDNF supports cell survival [14,15]. Once released into the synaptic cleft, p-BDNF binds preferentially to pan neurotrophin receptor p75 NTR for facilitating pro-apoptotic effects and long-term depression (LTD), while m-BDNF binds preferentially to both pre-and post-synaptic TrkB receptors for facilitating prosurvival effects and LTP [8,15].…”

“…Furthermore, BDNF p-BDNF and m-BDNF may have opposite biological effects; p-BDNF induces cell death whereas m-BDNF supports cell survival [14,15]. Once released into the synaptic cleft, p-BDNF binds preferentially to pan neurotrophin receptor p75 NTR for facilitating pro-apoptotic effects and long-term depression (LTD), while m-BDNF binds preferentially to both pre-and post-synaptic TrkB receptors for facilitating prosurvival effects and LTP [8,15]. p-BDNF and m-BDNF activate different intracellular messenger cascades and affect distinct cellular responses.…”