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 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.

Automated summary

This study found that brain-derived neurotrophic factor (BDNF) release enhances the transient depression of excitatory synaptic transmission caused by the anesthetic isoflurane. It also identified a common human BDNF gene polymorphism that contributes to the persistent inhibition effect of isoflurane on synaptic function. These findings highlight the importance of human genetic variation in the effects of anesthesia on synaptic plasticity and neurocognitive function.