A Common Human Brain-Derived Neurotrophic Factor Polymorphism Leads to Prolonged Depression of Excitatory Synaptic Transmission by Isoflurane in Hippocampal Cultures
Multiple presynaptic and postsynaptic targets have been identified for the reversible neurophysiological effects of general anesthetics on synaptic transmission and neuronal excitability. However, the synaptic mechanisms involved in persistent depression of synaptic transmission resulting in more pr...
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.927149/full |
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| author | Riley A. Williams Kenneth W. Johnson Francis S. Lee Francis S. Lee Francis S. Lee Hugh C. Hemmings Hugh C. Hemmings Jimcy Platholi Jimcy Platholi |
| author_facet | Riley A. Williams Kenneth W. Johnson Francis S. Lee Francis S. Lee Francis S. Lee Hugh C. Hemmings Hugh C. Hemmings Jimcy Platholi Jimcy Platholi |
| author_sort | Riley A. Williams |
| collection | DOAJ |
| description | Multiple presynaptic and postsynaptic targets have been identified for the reversible neurophysiological effects of general anesthetics on synaptic transmission and neuronal excitability. However, the synaptic mechanisms involved in persistent depression of synaptic transmission resulting in more prolonged neurological dysfunction following anesthesia are less clear. Here, we show that brain-derived neurotrophic factor (BDNF), a growth factor implicated in synaptic plasticity and dysfunction, enhances glutamate synaptic vesicle exocytosis, and that attenuation of vesicular BDNF release by isoflurane contributes to transient depression of excitatory synaptic transmission in mice. This reduction in synaptic vesicle exocytosis by isoflurane was acutely irreversible in neurons that release less endogenous BDNF due to a polymorphism (BDNF Val66Met; rs6265) compared to neurons from wild-type mice. These effects were prevented by exogenous application of BDNF. Our findings identify a role for a common human BDNF single nucleotide polymorphism in persistent changes of synaptic function following isoflurane exposure. These short-term persistent alterations in excitatory synaptic transmission indicate a role for human genetic variation in anesthetic effects on synaptic plasticity and neurocognitive function. |
| first_indexed | 2024-12-12T08:40:35Z |
| format | Article |
| id | doaj.art-4b40152ce4de4ef3a3b8a1bbfa65145d |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-12T08:40:35Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-4b40152ce4de4ef3a3b8a1bbfa65145d2022-12-22T00:30:47ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992022-06-011510.3389/fnmol.2022.927149927149A Common Human Brain-Derived Neurotrophic Factor Polymorphism Leads to Prolonged Depression of Excitatory Synaptic Transmission by Isoflurane in Hippocampal CulturesRiley A. Williams0Kenneth W. Johnson1Francis S. Lee2Francis S. Lee3Francis S. Lee4Hugh C. Hemmings5Hugh C. Hemmings6Jimcy Platholi7Jimcy Platholi8Department of Anesthesiology, Weill Cornell Medicine, New York, NY, United StatesDepartment of Pharmacology, Weill Cornell Medicine, New York, NY, United StatesDepartment of Pharmacology, Weill Cornell Medicine, New York, NY, United StatesDepartment of Psychiatry, Sackler Institute for Developmental Psychobiology, Weill Cornell Medicine, New York, NY, United StatesFeil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United StatesDepartment of Anesthesiology, Weill Cornell Medicine, New York, NY, United StatesDepartment of Pharmacology, Weill Cornell Medicine, New York, NY, United StatesDepartment of Anesthesiology, Weill Cornell Medicine, New York, NY, United StatesFeil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United StatesMultiple presynaptic and postsynaptic targets have been identified for the reversible neurophysiological effects of general anesthetics on synaptic transmission and neuronal excitability. However, the synaptic mechanisms involved in persistent depression of synaptic transmission resulting in more prolonged neurological dysfunction following anesthesia are less clear. Here, we show that brain-derived neurotrophic factor (BDNF), a growth factor implicated in synaptic plasticity and dysfunction, enhances glutamate synaptic vesicle exocytosis, and that attenuation of vesicular BDNF release by isoflurane contributes to transient depression of excitatory synaptic transmission in mice. This reduction in synaptic vesicle exocytosis by isoflurane was acutely irreversible in neurons that release less endogenous BDNF due to a polymorphism (BDNF Val66Met; rs6265) compared to neurons from wild-type mice. These effects were prevented by exogenous application of BDNF. Our findings identify a role for a common human BDNF single nucleotide polymorphism in persistent changes of synaptic function following isoflurane exposure. These short-term persistent alterations in excitatory synaptic transmission indicate a role for human genetic variation in anesthetic effects on synaptic plasticity and neurocognitive function.https://www.frontiersin.org/articles/10.3389/fnmol.2022.927149/fullBDNFisofluranesingle nucleotide polymorphismsynaptic vesicle exocytosissynaptic plasticity |
| spellingShingle | Riley A. Williams Kenneth W. Johnson Francis S. Lee Francis S. Lee Francis S. Lee Hugh C. Hemmings Hugh C. Hemmings Jimcy Platholi Jimcy Platholi A Common Human Brain-Derived Neurotrophic Factor Polymorphism Leads to Prolonged Depression of Excitatory Synaptic Transmission by Isoflurane in Hippocampal Cultures Frontiers in Molecular Neuroscience BDNF isoflurane single nucleotide polymorphism synaptic vesicle exocytosis synaptic plasticity |
| title | A Common Human Brain-Derived Neurotrophic Factor Polymorphism Leads to Prolonged Depression of Excitatory Synaptic Transmission by Isoflurane in Hippocampal Cultures |
| title_full | A Common Human Brain-Derived Neurotrophic Factor Polymorphism Leads to Prolonged Depression of Excitatory Synaptic Transmission by Isoflurane in Hippocampal Cultures |
| title_fullStr | A Common Human Brain-Derived Neurotrophic Factor Polymorphism Leads to Prolonged Depression of Excitatory Synaptic Transmission by Isoflurane in Hippocampal Cultures |
| title_full_unstemmed | A Common Human Brain-Derived Neurotrophic Factor Polymorphism Leads to Prolonged Depression of Excitatory Synaptic Transmission by Isoflurane in Hippocampal Cultures |
| title_short | A Common Human Brain-Derived Neurotrophic Factor Polymorphism Leads to Prolonged Depression of Excitatory Synaptic Transmission by Isoflurane in Hippocampal Cultures |
| title_sort | common human brain derived neurotrophic factor polymorphism leads to prolonged depression of excitatory synaptic transmission by isoflurane in hippocampal cultures |
| topic | BDNF isoflurane single nucleotide polymorphism synaptic vesicle exocytosis synaptic plasticity |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.927149/full |
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