New insights into the role of brain-derived neurotrophic factor in synaptic plasticity

Abstract

Substantial evidence indicates that brain-derived neurotrophic factor (BDNF) plays a crucial role in synaptic plasticity. Long-lasting synaptic plasticity is restricted to active synapses and requires new protein synthesis. Recent work has identified local protein synthesis as an important source for new protein during the expression of enduring synaptic plasticity. This review discusses recent progress in understanding the mechanisms that restrict the action of BDNF to active synapses and by which BDNF mediates chemical and structural modifications of individual synapses, placing an emphasis on the role of local protein synthesis in these processes.

Figure 1. BDNF and TrkB mRNA structure and subcellular localization

Transcripts encoding BDNF (A) and TrkB full length (TrkB-FL) and truncated (TrkB-T) (B) undergo alternative polyadenylation generating two mRNA species with identical coding sequences but different length 3’UTRs. The short form of BDNF mRNA is restricted to the soma, however the long form is targeted to the dendrites (An et al., 2008). Although not demonstrated, it is possible that this same sub-cellular localization mechanism is utilized for TrkB mRNAs as well.

Figure 2. Mechanisms of BDNF induced synaptic plasticity

In the non-stimulated state, dendritic spines remain “silent”: mRNAs are repressed in RNA granules, TrkB and AMPA receptors are held intracellularly, and actin dynamics leave the spine head in an immature form. Following synaptic activation, repressed mRNAs are disinhibited, TrkB is inserted into the plasma membrane, pro-BDNF and tPA are packaged either together or separately and released into the synaptic cleft, pro-BDNF is converted into BDNF by plasmin, and BDNF binds to TrkB on the local dendritic membrane. Activation of TrkB by BDNF increases translation of CaMKII, GluR1, Arc, and Limk1, leading to increased the formation and membrane insertion of the AMPA receptor and increased actin polymerization. TrkB signaling also induces phosphorylation of NMDA receptors, synapsin-1, p21 activated kinase, and cofilin, thus increasing receptor activity, vesicle-plasma membrane fusion and neurotransmitter release, and polymerization of actin, respectively.