The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus
Open accessAbstract
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.
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BDNFmet/met mice show decreased fluoxetine efficacy through impaired synaptic plasticity, including reduced theta-burst stimulation-induced LTP, impaired survival of newborn hippocampal cells, and a deficit in PFC synaptic transmission.
“subsequent experiments showed that this genetic variant decreased fluoxetine efficacy through impaired synaptic plasticity defined by a reduction of theta-burst stimulation-induced LTP as well as impairments in the survival of newborn cells in the hippocampus (Bath et al. 2012; Ninan et al. 2010) and a deficit in synaptic transmission in the PFC (Pattwell et al. 2012).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Ninan et al. 2010
The CA3-CA1 LTP results report reduced theta-burst stimulation-induced LTP in BDNF Met/Met mice compared with wild-type mice. Our copy does not establish that this impairment decreased fluoxetine efficacy or that newborn hippocampal cell survival was impaired. The PFC finding is attributed to Pattwell et al. (2012), not to this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThese mutant mice have reduced synaptic plasticity and synaptic transmission in both hippocampus and the medial prefrontal cortex.
“In addition, these mutant mice have reduced synaptic plasticity and synaptic transmission in both hippocampus and the medial prefrontal cortex (mPFC; Ninan et al., 2010; Pattwell et al., 2012).”
From BDNF - a key transducer of antidepressant effects (2016) · cites this paper as Ninan et al., 2010
The Abstract reports reduced NMDA receptor-dependent plasticity and NMDA receptor transmission in the hippocampus of BDNF Met/Met mice. It does not report findings for the medial prefrontal cortex. The CA3–CA1 LTP results also say basal synaptic neurotransmission was not markedly affected, so the transmission claim needs that qualification. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMice carrying the Val66Met mutation in the Bdnf gene show LTP deficits similar to BDNF-deficient mice.
“Similar findings have been found in mice carrying the Val66Met mutation in the Bdnf gene74, which corresponds to a common human Bdnf gene polymorphism that alters the amino acid valine to methionine in the position 66 of the BDNF pro-region, leading to impaired activity-dependent BDNF release75.”
From Neuronal plasticity and neurotrophic factors in drug responses (2017) · cites this paper as [74]
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References 41 · Cited by 180
- Authors
- Ninan, I., Bath, K. G., Dagar, K., Perez-Castro, R., Plummer, M. R., Lee, F. S., & Chao, M. V.
- Affiliations
- NYU Langone Health (US)
- Cornell University (US)
- New York University (US)
- Rutgers, The State University of New Jersey (US)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-06-30
- Volume
- 30
- Issue
- 26
- Pages
- 8866-8870
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2911131
- OpenAlex
- W2067017935
- Cited by
- 180
- References
- 41
- Citations by year
- 2025: 6 · 2024: 5 · 2023: 6 · 2022: 10 · 2021: 13 · 2020: 15 · 2019: 9 · 2018: 5 · 2017: 16 · 2016: 13 · 2015: 19 · 2014: 20 · 2013: 19 · 2012: 13
- FWCI
- 5.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- New York Community Trust
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (MH079513, NS-21072)
- National Institute of Mental Health (P50MH079513, MH079513, R25MH060478, MH060478)
- National Institute of Neurological Disorders and Stroke (R01NS021072, NS052819, R01NS052819, R56NS021072)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- BDNF Val66Met polymorphism, brain-derived neurotrophic factor, NMDA receptor, synaptic plasticity, long-term potentiation, long-term depression, hippocampus, CA3-CA1 synapses, glutamatergic neurotransmission, CA1 pyramidal neurons, BDNF release
- MeSH terms
- Aging, Animals, Female, Hippocampus, Mice, Inbred C57BL, Mice, Transgenic, Synaptic Transmission, Neuronal Plasticity, Neurons, Polymorphism, Genetic, Synapses, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Pyramidal Cells, Receptors, Metabotropic Glutamate, Glutamic Acid, Brain-Derived Neurotrophic Factor, Long-Term Synaptic Depression, Mice
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