A Common Human Brain-Derived Neurotrophic Factor Polymorphism Leads to Prolonged Depression of Excitatory Synaptic Transmission by Isoflurane in Hippocampal Cultures

Front Mol Neurosci. 2022 Jun 23;15:927149. doi: 10.3389/fnmol.2022.927149. eCollection 2022.


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.

Keywords: BDNF; isoflurane; single nucleotide polymorphism; synaptic plasticity; synaptic vesicle exocytosis.