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

Overview

Journal J Neurosci

Specialty Neurology

Date 2010 Jul 2

PMID 20592208

Citations 96

Authors

Ipe Ninan

Kevin G Bath

Karishma Dagar

Rosalia Perez-Castro

Mark R Plummer

Francis S Lee

Moses V Chao

Affiliations

Soon will be listed here.

Abstract

The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF(Met/Met) mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in NMDA receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF(Met/Met) mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF(Met/Met) mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus.

Citing Articles

BDNF levels in serum and CSF are associated with clinicoradiological characteristics of aggressive disease in MS patients.

Maiworm M, Koerbel K, Anschutz V, Jakob J, Schaller-Paule M, Schafer J J Neurol. 2025; 272(2):147.

PMID: 39812717 PMC: 11735549. DOI: 10.1007/s00415-024-12875-3.

Median raphe glutamatergic neuron-mediated enhancement of GABAergic transmission and suppression of long-term potentiation in the hippocampus.

Stinson H, Ninan I Heliyon. 2024; 10(19):e38192.

PMID: 39386853 PMC: 11462361. DOI: 10.1016/j.heliyon.2024.e38192.

Interaction between BDNF Val66Met polymorphism and mismatch negativity for working memory capacity in schizophrenia.

Hou W, Qin X, Li H, Wang Q, Ding Y, Chen X Schizophrenia (Heidelb). 2024; 10(1):70.

PMID: 39174571 PMC: 11341781. DOI: 10.1038/s41537-024-00493-x.

The relevance of BDNF for neuroprotection and neuroplasticity in multiple sclerosis.

Maiworm M Front Neurol. 2024; 15:1385042.

PMID: 39148705 PMC: 11325594. DOI: 10.3389/fneur.2024.1385042.

The impact of BDNF and CD4 + T cell crosstalk on depression.

Mickael M, Kubick N, Dragan M, Atanasov A, Lawinski M, Paszkiewicz J Immunol Res. 2024; 72(5):883-894.

PMID: 38980567 DOI: 10.1007/s12026-024-09514-4.

References

Bekinschtein P, Cammarota M, Izquierdo I, Medina J . BDNF and memory formation and storage. Neuroscientist. 2007; 14(2):147-56. DOI: 10.1177/1073858407305850. View

Tyler W . BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci. 2001; 21(12):4249-58. PMC: 2806848. View

Morgan S, Teyler T . Electrical stimuli patterned after the theta-rhythm induce multiple forms of LTP. J Neurophysiol. 2001; 86(3):1289-96. DOI: 10.1152/jn.2001.86.3.1289. View

Gladding C, Fitzjohn S, Molnar E . Metabotropic glutamate receptor-mediated long-term depression: molecular mechanisms. Pharmacol Rev. 2009; 61(4):395-412. PMC: 2802426. DOI: 10.1124/pr.109.001735. View

Caldeira M, Melo C, Pereira D, Carvalho R, Carvalho A, Duarte C . BDNF regulates the expression and traffic of NMDA receptors in cultured hippocampal neurons. Mol Cell Neurosci. 2007; 35(2):208-19. DOI: 10.1016/j.mcn.2007.02.019. View

Serulle Y, Zhang S, Ninan I, Puzzo D, McCarthy M, Khatri L . A GluR1-cGKII interaction regulates AMPA receptor trafficking. Neuron. 2007; 56(4):670-88. PMC: 2153457. DOI: 10.1016/j.neuron.2007.09.016. View

Levine E, Crozier R, Black I, Plummer M . Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-D-aspartic acid receptor activity. Proc Natl Acad Sci U S A. 1998; 95(17):10235-9. PMC: 21491. DOI: 10.1073/pnas.95.17.10235. View

Kumar A, Foster T . Shift in induction mechanisms underlies an age-dependent increase in DHPG-induced synaptic depression at CA3 CA1 synapses. J Neurophysiol. 2007; 98(5):2729-36. DOI: 10.1152/jn.00514.2007. View

Zakharenko S, Zablow L, Siegelbaum S . Visualization of changes in presynaptic function during long-term synaptic plasticity. Nat Neurosci. 2001; 4(7):711-7. DOI: 10.1038/89498. View

10.

Massey P, Bashir Z . Long-term depression: multiple forms and implications for brain function. Trends Neurosci. 2007; 30(4):176-84. DOI: 10.1016/j.tins.2007.02.005. View

11.

Egan M, Kojima M, Callicott J, Goldberg T, Kolachana B, Bertolino A . The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003; 112(2):257-69. DOI: 10.1016/s0092-8674(03)00035-7. View

12.

Yano H, Ninan I, Zhang H, Milner T, Arancio O, Chao M . BDNF-mediated neurotransmission relies upon a myosin VI motor complex. Nat Neurosci. 2006; 9(8):1009-18. DOI: 10.1038/nn1730. View

13.

Malenka R, Bear M . LTP and LTD: an embarrassment of riches. Neuron. 2004; 44(1):5-21. DOI: 10.1016/j.neuron.2004.09.012. View

14.

Rybakowski J . BDNF gene: functional Val66Met polymorphism in mood disorders and schizophrenia. Pharmacogenomics. 2008; 9(11):1589-93. DOI: 10.2217/14622416.9.11.1589. View

15.

Xiao M, Zhou Q, Nicoll R . Metabotropic glutamate receptor activation causes a rapid redistribution of AMPA receptors. Neuropharmacology. 2001; 41(6):664-71. DOI: 10.1016/s0028-3908(01)00134-4. View

16.

Bear M, Abraham W . Long-term depression in hippocampus. Annu Rev Neurosci. 1996; 19:437-62. DOI: 10.1146/annurev.ne.19.030196.002253. View

17.

Verhagen M, van der Meij A, van Deurzen P, Janzing J, Arias-Vasquez A, Buitelaar J . Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity. Mol Psychiatry. 2008; 15(3):260-71. DOI: 10.1038/mp.2008.109. View

18.

Zucker R . Short-term synaptic plasticity. Annu Rev Neurosci. 1989; 12:13-31. DOI: 10.1146/annurev.ne.12.030189.000305. View

19.

Chen G, Harata N, Tsien R . Paired-pulse depression of unitary quantal amplitude at single hippocampal synapses. Proc Natl Acad Sci U S A. 2004; 101(4):1063-8. PMC: 327151. DOI: 10.1073/pnas.0307149101. View

20.

Malenka R, Nicoll R . Long-term potentiation--a decade of progress?. Science. 1999; 285(5435):1870-4. DOI: 10.1126/science.285.5435.1870. View