Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease

Abstract

Brain-derived neurotrophic factor (BDNF) is a prototypic neurotrophin that regulates diverse developmental events from the selection of neural progenitors to the terminal dendritic differentiation and connectivity of neurons. We focus here on activity-dependent synaptic regulation by BDNF and its receptor, full length TrkB. BDNF-TrkB signaling is involved in transcription, translation, and trafficking of proteins during various phases of synaptic development and has been implicated in several forms of synaptic plasticity. These functions are carried out by a combination of the three signaling cascades triggered when BDNF binds TrkB: The mitogen-activated protein kinase (MAPK), the phospholipase Cgamma (PLC PLCgamma), and the phosphatidylinositol 3-kinase (PI3K) pathways. MAPK and PI3K play crucial roles in both translation and/or trafficking of proteins induced by synaptic activity, whereas PLCgamma regulates intracellular Ca(2+) that can drive transcription via cyclic AMP and a protein kinase C. Conversely, the abnormal regulation of BDNF is implicated in various developmental and neurodegenerative diseases that perturb neural development and function. We will discuss the current state of understanding BDNF signaling in the context of synaptic development and plasticity with a focus on the postsynaptic cell and close with the evidence that basic mechanisms of BDNF function still need to be understood to effectively treat genetic disruptions of these pathways that cause devastating neurodevelopmental diseases.

Figure 1

Binding of BDNF activates PLCγ, PI3K and MAPK pathways.

Figure 2. BDNF-TrkB signaling Regulates Multiple Events through PLCγ, PI3K and MAPK pathways

(a) PI3K pathway regulates trafficking and PSD-95 to a synapse and cAMP regulates formation of synaptic PSD-95-TrkB complex. (b) BDNF-TrkB signaling activates MAPK/Erk, increasese cAMP and activate CREB-regulated gene transcription. (c) BDNF-TrkB signaling regulates protein translation through both MAPK/Erk and PI3K-Akt-mTOR pathways. PI3K-Akt also regulates protein trafficking in ER and Golgi. (d) A diagram showing BDNF-TrkB signaling regulates multiple molecular events through three pathways in parallel.

Figure 3. BDNF bead application to a short dendritic segment facilitates PSD-95-GFP FRAP throughout the dendritic tree of locally-stimulated neurons

(a) (Top row) BDNF covalently linked to a bead (pseudo-colored red) was placed in contact with one dendritic branch and a dendritic segment nearby (white square) was bleached. (Middle row) A segment of a completely separate dendrite was bleached after a BDNF-coated bead was applied. (Bottom row) A group of BDNF-coated beads was placed near a dendrite without contact. Scale, 10 µm. (b) Magnified images of dendrites inside the white squares in Fig. 6(a). The branches from a neuron contacting the BDNF-coated bead or a separate dendritic branch from a neuron with a BNDF-coated bead contacting another one of its dendrites, show a more pronounced FRAP of PSD-95-GFP than a branch from the neuron with near-by beads that have no dendritic contact. Each image corresponds to a 21 µm × 21 µm bleached frame. Filled arrowheads in the second row identify weak puncta and their recovery in a dendrite that was expressing relatively low intensity PSD-95 puncta. (c) FRAP graph summarizing the results of the dendrite-wide BDNF-bead-mediated PSD-95-GFP FRAP. Application of BDNF-coated beads to one dendrite of transfected neurons showed significantly facilitated PSD-95-GFP FRAP on distant dendrites of the same cells. Beads coated only with BSA and touching a dendrite had no effect above baseline on PSD-95-GFP FRAP in the dendrites of the contacted cell. Dendrites of nearby cells that were not contacted by beads covalently coated with BDNF showed the same baseline FRAP response seen with the BSA-coated beads. This lack of effect indicates that the PSD-95-GFP FRAP shown by dendrites distant from the one contacted by the BDNF bead were not driven by trace amounts of BDNF escaping from the bead. FRAP with bead treatments are shown against shaded areas reflecting the difference between baseline FRAP and FRAP with BDNF in the perfusion fluid. P=0.02 Error bar, s.e.m. (Adopted from Yoshii and Constantine-Paton, 2007)

Figure 4. A model for rapid, dendrite-wide, sensitization for synaptic potentiation conveyed by local NMDAR and BDNF activity-driven-PSD-95 trafficking to synapses throughout the neuron

(a) Strong local NMDAR stimulation recruits TrkB to synapses, inserts AMPARs into extrasynaptic membrane, and initiates BDNF signaling. (b) Mature BDNF near the synapse stimulates TrkB. TrkB activates PI3K and Akt resulting in facilitated PSD-95 localization to the Golgi and microtubule based transport along dendrites. (c) An increased probability (sensitization) of LTP occurs at synapses throughout the dendritic tree as a result of dendrite-wide trafficking of PSD-95 from the Golgi. Synapses with a surplus of PSD-95 can readily bind AMPAR-stargazin complexes at the synapse and consequently strengthen that contact if a young synapse activates NMDARs sufficiently to drive AMPAR-stargazin complexes to the extrasynaptic membrane. (Adopted from Yoshii and Constantine-Paton, 2007)