Classic effects of brain-derived neurotrophic factor (BDNF) include promoting neuronal viability, differentiation, migration, and dendritic arborization. In addition to these established actions, an evolving body of literature describes an important role at the synapse, where BDNF affects development, function, and plasticity.1, 2 Recently, studies of the synaptic actions of BDNF have focused on activity-dependent changes in neuronal BDNF expression.3 Activity-dependent changes are those that occur following synaptic transmission, when Ca2+ influx induces transcription factors to bind calcium-response elements (CaREs) in the nucleus. Although the importance of activity-regulated BDNF expression for brain development and neuronal function is unquestioned, direct evidence supporting its role in synaptic plasticity has been difficult to obtain.
To address this challenge, Hong et al. conducted a series of genetic studies in which individual CaREs in promoter IV of the Bdnf gene were blocked using knock-in mutations.4 Promoter IV is known to be important for synaptic plasticity, both developmentally and in the adult brain. One intriguing finding from this report was observed in CREmKI mice, where the CaRE that regulates activity-dependent Bdnf mRNA expression via the CREB transcription factor (CaRE3/CRE) was specifically blocked. Unlike mice lacking BDNF, which are not viable, CREmKI mice developed normally, and were behaviorally indistinguishable from their control littermates. However, the levels of activity-induced Bdnf mRNA expression were less than 50% of wild-type control values both in embryonic cultures of CREmKI cortical neurons and in adult visual cortex. This specific reduction in activity-induced Bdnf expression decreased inhibitory synapse density in both dissociated cultures of CREmKI neurons and in vivo (visual cortex). These novel data suggest that BDNF influences homeostatic plasticity by modulating the balance between excitatory and inhibitory signaling in the brain. This hypothesis was supported by a study which showed that disruption of promoter IV-induced Bdnf expression specifically impaired inhibitory synaptic signaling in the prefrontal cortex.5
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|Activity-dependent BDNF Expression Influences Homeostatic Plasticity. Excitatory neuronal activity increases postsynaptic BDNF levels via Ca2+ -dependent transcription factors. For example, CREB phosphorylated on serine 133 binds to CaRE3/CRE following coactivation by CREB binding protein (CBP). Postsynaptic release of BDNF subsequently promotes the formation of inhibitory GABAergic synapses. The BDNF precursor, pro-BDNF is also an actively secreted molecule that affects synaptic plasticity during development.12, 13|
Neurodegeneration and synaptic loss characterize many neurological disorders including Alzheimer's disease (AD), the most common form of dementia.6 To investigate the potential therapeutic benefits of BDNF administration, Nagahara and colleagues designed experiments to deliver BDNF into the brains of rodents and primates.7 The authors targeted the cortex and hippocampus, two brain regions that are severely affected during AD. Lentiviral vectors constitutively expressing Bdnf-GFP were injected into the entorhinal cortex of a transgenic mouse model of AD. BDNF delivery reversed synaptic loss, as measured by the expression of synaptic markers. In parallel, infusion of recombinant BDNF into the entorhinal cortex of cognitively impaired aged rats improved spatial learning and memory performance in the Morris water maze. These positive findings extended to primate studies where BDNF delivery significantly improved visuospatial discrimination in aged impaired monkeys. The therapeutic potential of BDNF may also apply to Huntington's disease (HD),8 since increased endogenous BDNF expression rescued synaptic plasticity in a mouse model of HD.9
Pharmacologically harnessing the beneficial synaptic effects of BDNF will require a better understanding of the underlying mechanism(s) of its action. Dean et al. recently described the role of Synaptotagmin-IV (syt-IV) in BDNF release.10 In this study, the authors used co-cultures of wild-type and Syt-IV-/- mouse hippocampal neurons to investigate the mode of synaptic BDNF release. Results from these experiments showed that neuronal activity upregulates the expression of syt-IV, and syt-IV localizes to BDNF-containing vesicles. Functionally, syt-IV was found to negatively regulate the release of BDNF, an effect which was shown to modulate synaptic function and plasticity. Interestingly, these studies suggested that axons and dendrites have distinct modes of BDNF release, and that postsynaptic BDNF release may act as a retrograde signal to modify presynaptic vesicle fusion.10 In support of this hypothesis, transcellular retrograde signaling by BDNF was shown to increase hippocampal neuron GABA release via presynaptic TrkB receptors.11