A common human brain-derived neurotrophic factor polymorphism leads to sustained depression of excitatory synaptic transmission by isoflurane in hippocampus

Abstract

AbstractMultiple 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 was irreversible in neurons that release less endogenous BDNF due to a polymorphism (BDNF Val66Met) compared to wild-type mouse hippocampal neurons following isoflurane exposure. These effects were prevented by exogenous application of BDNF. Our findings identify a role for a common human BDNF single nucleotide polymorphism (Val66Met; rs6265) in persistent changes of synaptic function following isoflurane exposure. These persistent alterations in excitatory synaptic transmission have important implications for the role of genotype in anesthetic effects on synaptic plasticity and neurocognitive function.