In this study, we show that the function of BDNF as an activator of synaptic activity underlies its ability to promote survival of hippocampal neurons against oxidative stress and excitotoxicity. The neuroprotective mechanism triggered by BDNF treatment is mediated by synaptic NMDA receptor activation, causing a nuclear-calcium-regulated genomic response, which via increased inhba expression, secretion into the extracellular space, and activation of ActR leads to a reduction in neurotoxic extrasynaptic NMDA-receptor-mediated calcium influx, which shields mitochondria from excitotoxicity-associated dysfunction ( Figure 7 E). These findings challenge the prevalent view that BDNF-evoked PI3K/Akt and ERK1/2 signaling and the activation of downstream effector molecules, such as Bad (), are primarily responsible for the neuroprotective functions of BDNF (). Indeed, a lack of contribution of either ERK1/2 or PI3K or both to BDNF-induced neuroprotection has been suggested previously (). Such discrepancies may be due to differences in the toxic stimulus, the developmental state of the tissue, and possibly also non-selective pharmacological actions of the ERK1/2 and PI3K inhibitors used (). For example, synaptic connectivity, which is present in our culture networks at days in vitro (DIV) 10–12 () but absent in 6- to 7-day-old cultures (data not shown), is necessary for the nuclear calcium signaling and transcriptional responses to BDNF.

Our results revealed that BDNF is not only a component of activity-dependent neuroprotection () but that it exerts its neuroprotective function in hippocampal neurons principally through stimulating synaptic activity, the generation of nuclear calcium signals, and the induction of genomic responses. One important implication of these findings is that other biological effects of BDNF, for instance during development or in diseases, may have to be viewed in light of the ability of BDNF to promote synaptic activity. BDNF-induced long-term survival may not primarily result from its neurotrophic actions as previously thought but could rather reflect the consequence of activity-dependent neuroprotection, which together with the effect of BDNF to promote neuronal differentiation and synaptogenesis () and area-specific dendritic growth () may support the integration of isolated and initially possibly vulnerable neurons into functionally stable neuronal networks.

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In light of the observed links between BDNF, neuronal activity, and synaptic NMDA receptors, it may be necessary to reassess the process through which BDNF or the lack of it contributes to neuropathology. Previous studies argue that neuronal cell death in Alzheimer’s disease (AD), Huntington’s disease (HD), or Parkinson’s disease (PD) occur as a consequence of disease-specific factors, which lead to a deficiency in neurotrophic support by BDNF (). Our findings suggest that reduced levels of BDNF could, in addition to decreasing trophic support, compromise neuronal activity, the balance between synaptic versus extrasynaptic NMDA receptor signaling, and the ability to generate nuclear calcium signals, which are essential for the activation of neuroprotective genes. Consequently, neurons deprived of BDNF and BDNF-evoked activity may be more vulnerable to cellular stresses due to engagement of neurotoxic extrasynaptic NMDA receptor signaling and reduced expression of activity- and calcium-signal-regulated genes critical, for example, for the stabilization and strengthening of mitochondrial functions () and/or for the initiation and maintenance of antioxidant defenses (). Because BDNF can enhance the efficacy of synaptic transmission () but itself is also subject to regulation by neuronal activity (), an initial decrease in BDNF levels caused by disease-specific factors () may trigger a self-reinforcing gradual decline of synaptic activity and network function, leading to a pathological state of compromised cell health. Therapeutic intervention aimed at enhancing BDNF signaling may break this vicious circle. However, local administration of BDNF in clinical settings has proven only moderately successful for several reasons including the short half-life of BDNF, its poor blood-brain barrier penetration, and the unwanted side effects such as severe cognitive impairment or even epileptic seizures (). The implication of the concept of “BDNF as an enhancer of synaptic activity- and calcium-regulated processes” is that possible treatments of neurodegenerative diseases would not necessarily need to include the application of BDNF. Therapeutic strategies that support and enhance synaptic activity by using either pharmacological means or even mental exercises and living an active lifestyle may prove useful. In line with this, optogenetic stimulation has recently been shown to aid recovery after stroke () and the benefits of physical exercise on cognition are mediated by BDNF (). Indeed, activity-induced transcription of bdnf may create the positive feedback loop required for sustained neuroprotection and survival, circumventing the difficulties and side effects associated with BDNF administration. In addition, the delivery of downstream targets of BDNF and synaptic activity, in particular inhba/activin A, as well as the development of agonists of ActR signaling may prove an effective strategy to boost neuroprotection and combat neuron loss in neurodegenerative diseases including AD, HD, and PD, in which impaired synaptic activity, imbalanced synaptic versus extrasynaptic NMDA receptor activation, and dysfunctional BDNF signaling are early hallmarks (). Encouraging results have already been obtained using activin A as a neuroprotective agent in a rat lesion model of HD (). Recent work demonstrated that overexpression of mutant huntingtin induces phosphorylation of the NR2B subunit at tyrosine residue 1472 in vitro (), sensitizes NMDA receptors, and induces excitotoxicity in vivo (), indicating that cell loss in HD (and perhaps also in other neurodegenerative diseases;) may result from a shift in the balance of NMDA receptor signaling from the survival-promoting synaptic NMDA receptor toward extrasynaptic NMDA receptors that initiate cell death pathways (). By showing that BDNF/inhba signaling regulates and restores the balance in NMDA receptor signaling by affecting phosphorylation of the NR2B subunit at tyrosine residue 1472 and reducing the toxic, extrasynaptic NMDA-receptor-induced calcium influx, our data causally link these findings by delivering an explanation as to how activin A may rescue BDNF-deficient neurons from neuronal dysfunction and cell death associated with, or caused by, an imbalance in extrasynaptic versus synaptic NMDA receptor signaling. It describes an alternative BDNF-dependent neuroprotective pathway involving the activation of synaptic NMDA receptors, nuclear calcium signaling, and the induction and expression of activin A to regulate the balance between extrasynaptic versus synaptic NMDA receptor signaling and thus provide a mechanism that may help to understand pathological processes underlying HD and other neurodegenerative diseases.