The BDNF Val66Met Polymorphism Impairs NMDA Receptor-Dependent Synaptic Plasticity in the Hippocampus

Ninan, Ipe; Bath, Kevin G.; Dagar, Karishma; Perez-Castro, Rosalia; Plummer, Mark R.; Lee, Francis S.; Chao, Moses V.

doi:10.1523/jneurosci.1405-10.2010

Cited by 163 publications

(146 citation statements)

References 42 publications

Supporting

Mentioning

134

Contrasting

Order By: Relevance

“…In agreement with these findings, LTP is significantly inhibited when highfrequency stimulation (HFS) is performed in the presence of the BDNF and NT4 (neurotrophin-4) scavenger TrkB-IgG or with antiTrkB antibodies (Chen et al, 1999;Figurov et al, 1996;Kang et al, 1997;Korte et al, 1998). The Val66Met polymorphism in the Bdnf gene which results in a defect in regulated release of BDNF and affects episodic memory (Egan et al, 2003) also leads to an impairment of LTP (Ninan et al, 2010), further indicating a role for BDNF in this form of plasticity in the hippocampus. However, at this point the timing and relative role of the pre-and post-synaptic region in the release of BDNF still remains to be elucidated.…”

Section: Bdnf and Ltp In The Hippocampusmentioning

confidence: 65%

BDNF-induced local protein synthesis and synaptic plasticity

2014

View full text Add to dashboard Cite

a b s t r a c tBrain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and longterm potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-g (PLC-g) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin acts at pre-and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short-and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation.This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

show abstract

Section: Bdnf and Ltp In The Hippocampusmentioning

confidence: 65%

BDNF-induced local protein synthesis and synaptic plasticity

2014

View full text Add to dashboard Cite

show abstract

“…We have recently described significant effects of this SNP on synaptic transmission and plasticity at the CA3-CA1 synapse (Ninan et al, 2010). To our knowledge, these are the first studies to identify impairments in synaptic plasticity resulting from the BDNF Val66Met SNP in the DG.…”

Section: Discussionmentioning

confidence: 84%

“…These results suggest that fluoxetine affects plasticity by mechanisms other than neurogenesis. The lack of effect of fluoxetine on BDNF levels or a potential alteration of synaptic function might be responsible for fluoxetine-resistant LTP impairment in BDNF Met/Met mice (Colino and Malenka, 1993;Ninan et al, 2010). BDNF has reliably been shown to be a significant promoter of synaptic excitability and LTP within the hippocampus (Minichiello, 2009) and the loss of TrkB from newborn neurons in this region significantly impact LTP (Bergami et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

Bath

Jing

Dincheva

et al. 2012

Neuropsychopharmacol

152

114

View full text Add to dashboard Cite

Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRIinduced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF Val/Val ) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF Met/Met ). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF Met/Met mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF Met/Met mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.

show abstract

“…BDNF is active in the hippocampus and cortex where it regulates neuronal excitability, synaptic plasticity, long-term potentiation (LTP), and neurogenesis (Acheson et al 1995;Huang & Reichardt 2001;Ninan et al 2010). BDNF is known to bind the tyrosine kinase receptor B (TrkB) receptor, modulating neurotransmitter receptors to activate various kinase signaling pathways of phosphoinositide 3-kinase/AKT (PI3K/AKT), extracellular signal-regulated kinases (ERK1/ 2), mitogen-activated protein kinase (MAPK), or calcium/ calmodulin dependent protein kinase (CaMKII), and inducing phospho-CREB-mediated transcription (Mai et al 2002;Garoflos et al 2005;Luikart et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Low-intensity treadmill exercise and bright light upregulate brain-derived neurotrophic factor expression and intracellular signaling pathway in rat hippocampus and cerebral cortex

Kwon

Song

Kim

et al. 2014

Animal Cells and Systems

View full text Add to dashboard Cite

Continuous exercise and bright light affect brain function, particularly in seasonal affective disorders. However, the underlying mechanism of action remains unclear. In this study, we examined whether low-intensity treadmill exercise and 4 weeks of bright light exposure change the expression of brain-derived neurotrophic factor (BDNF), phosphoinositide 3-kinase/AKT (PI3K/AKT) pathway, protein kinase C (PKC), extracellular signalregulated kinases (ERK1/2), cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), vascular endothelial growth factor (VEGF), and glycogen synthase kinase-3β (GSK-3β) in the brain of 5-week old Sprague-Dawley male rats by performing western blot analysis. We demonstrated that BDNF expression significantly increased with exercise and light exposure compared to a control group. Moreover, we found that the expression levels of PI3K, PKC, p-ERK1/2, p-CREB, p-AKT, and VEGF increased significantly in the hippocampus and cortex with exercise and light exposure compared to the levels from a control group. However, phosphorylated GSK-3β level was unchanged, and even slightly decreased with exercise and light exposure. These results suggest that low-intensity treadmill exercise and bright light exposure induce BDNF expression and activate its downstream kinase signaling pathway, which in turn activate CREB-mediated transcription of neurotrophic factors and may stimulate neurogenesis and improve neuronal functions.

show abstract

The BDNF Val66Met Polymorphism Impairs NMDA Receptor-Dependent Synaptic Plasticity in the Hippocampus

Cited by 163 publications

References 42 publications

BDNF-induced local protein synthesis and synaptic plasticity

BDNF-induced local protein synthesis and synaptic plasticity

BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

Low-intensity treadmill exercise and bright light upregulate brain-derived neurotrophic factor expression and intracellular signaling pathway in rat hippocampus and cerebral cortex

Contact Info

Product

Resources

About