Multiple Approaches to Investigate the Transport and Activity-Dependent Release of BDNF and Their Application in Neurogenetic Disorders

Hartmann, David A.; Drummond, Jana B.; Handberg, Erik; Ewell, Sharday; Pozzo-Miller, Lucas

doi:10.1155/2012/203734

Cited by 22 publications

(29 citation statements)

References 86 publications

(137 reference statements)

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“…In this SNP, val at position 66 is changed to met in the pro region of proBDNF (Lu, 2003b; Hartmann et al, 2012). This SNP does not affect the expression levels or intracellular signaling triggered by the mature BDNF protein.…”

Section: Discussionmentioning

confidence: 99%

The BDNF val-66-met Polymorphism Affects Neuronal Morphology and Synaptic Transmission in Cultured Hippocampal Neurons from Rett Syndrome Mice

García

Ewalt

et al. 2017

Front. Cell. Neurosci.

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Brain-derived neurotrophic factor (Bdnf) has been implicated in several neurological disorders including Rett syndrome (RTT), an X-linked neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). The human BDNF gene has a single nucleotide polymorphism (SNP)—a methionine (met) substitution for valine (val) at codon 66—that affects BDNF’s trafficking and activity-dependent release and results in cognitive dysfunction. Humans that are carriers of the met-BDNF allele have subclinical memory deficits and reduced hippocampal volume and activation. It is still unclear whether this BDNF SNP affects the clinical outcome of RTT individuals. To evaluate whether this BDNF SNP contributes to RTT pathophysiology, we examined the consequences of expression of either val-BDNF or met-BDNF on dendrite and dendritic spine morphology, and synaptic function in cultured hippocampal neurons from wildtype (WT) and Mecp2 knockout (KO) mice. Our findings revealed that met-BDNF does not increase dendritic growth and branching, dendritic spine density and individual spine volume, and the number of excitatory synapses in WT neurons, as val-BDNF does. Furthermore, met-BDNF reduces dendritic complexity, dendritic spine volume and quantal excitatory synaptic transmission in Mecp2 KO neurons. These results suggest that the val-BDNF variant contributes to RTT pathophysiology, and that BDNF-based therapies should take into consideration the BDNF genotype of the RTT individuals.

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Section: Discussionmentioning

confidence: 99%

The BDNF val-66-met Polymorphism Affects Neuronal Morphology and Synaptic Transmission in Cultured Hippocampal Neurons from Rett Syndrome Mice

García

Ewalt

et al. 2017

Front. Cell. Neurosci.

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“…BDNF is a principal neurotrophic factor during brain development as well as in the adult, and has been associated with neuroprotective benefit in a broad range of CNS traumatic and neurodegenerative disorders, including stroke (Zaleska et al, 2009;Nagahara and Tuszynski, 2011;Hartmann et al, 2012). In fact, endogenous BDNF has been implicated in neuronal survival following ischemia (Larsson et al, 1999;Ke et al, 2011), and treatment with exogenous BDNF postischemia has been shown to be neuroprotective and contribute to recovery and neural regeneration (Schäbitz et al, 2007;for review, see Zaleska et al, 2009;Rothman and Mattson, 2013).…”

Section: Discussionmentioning

confidence: 99%

BDNF Mediates Neuroprotection against Oxygen-Glucose Deprivation by the Cardiac Glycoside Oleandrin

et al. 2014

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We have previously shown that the botanical drug candidate PBI-05204, a supercritical CO 2 extract of Nerium oleander, provides neuroprotection in both in vitro and in vivo brain slice-based models for focal ischemia (Dunn et al., 2011). Intriguingly, plasma levels of the neurotrophin BDNF were increased in patients treated with PBI-05204 in a phase I clinical trial (Bidyasar et al., 2009). We thus tested the hypothesis that neuroprotection provided by PBI-05204 to rat brain slices damaged by oxygen-glucose deprivation (OGD) is mediated by BDNF. We found, in fact, that exogenous BDNF protein itself is sufficient to protect brain slices against OGD, whereas downstream activation of TrkB receptors for BDNF is necessary for neuroprotection provided by PBI-05204, using three independent methods. Finally, we provide evidence that oleandrin, the principal cardiac glycoside component of PBI-05204, can quantitatively account for regulation of BDNF at both the protein and transcriptional levels. Together, these findings support further investigation of cardiac glycosides in providing neuroprotection in the context of ischemic stroke.

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“…Although it is desired to quantify directly the absolute amounts of BDNF and proBDNF released (setting aside their cellular contents) to prove their involvement in RISE and LOSS, such quantification is still difficult, since released BDNF is quickly bound to TrkB, p75 NTR and the extracellular matrices 32 and proBDNF is rapidly converted to BDNF 15 . So we chose a strategy to use function-blocking antibodies against endogenous neurotrophin receptors.…”

Section: Discussionmentioning

confidence: 99%

Involvement of TrkB- and p75NTR-signaling pathways in two contrasting forms of long-lasting synaptic plasticity

Sakuragi

Tominaga-Yoshino

Ogura

2013

Sci Rep

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The repetition of experience is often necessary to establish long-lasting memory. However, the cellular mechanisms underlying this repetition-dependent consolidation of memory remain unclear. We previously observed in organotypic slice cultures of the rodent hippocampus that repeated inductions of long-term potentiation (LTP) led to a slowly developing long-lasting synaptic enhancement coupled with synaptogenesis. We also reported that repeated inductions of long-term depression (LTD) produced a long-lasting synaptic suppression coupled with synapse elimination. We proposed these phenomena as useful in vitro models for analyzing repetition-dependent consolidation. Here, we hypothesized that the enhancement and suppression are mediated by the brain-derived neurotrophic factor (BDNF)-TrkB signaling pathway and the proBDNF-p75NTR pathway, respectively. When we masked the respective pathways, reversals of the enhancement and suppression resulted. These results suggest the alternative activation of the p75NTR pathway by BDNF under TrkB-masking conditions and of the TrkB pathway by proBDNF under p75NTR-masking conditions, thus supporting the aforementioned hypothesis.

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Multiple Approaches to Investigate the Transport and Activity-Dependent Release of BDNF and Their Application in Neurogenetic Disorders

Cited by 22 publications

References 86 publications

The BDNF val-66-met Polymorphism Affects Neuronal Morphology and Synaptic Transmission in Cultured Hippocampal Neurons from Rett Syndrome Mice

The BDNF val-66-met Polymorphism Affects Neuronal Morphology and Synaptic Transmission in Cultured Hippocampal Neurons from Rett Syndrome Mice

BDNF Mediates Neuroprotection against Oxygen-Glucose Deprivation by the Cardiac Glycoside Oleandrin

Involvement of TrkB- and p75NTR-signaling pathways in two contrasting forms of long-lasting synaptic plasticity

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