General anesthetics cause a reversible loss of consciousness and produce a behaviorally inert state that makes surgery possible. Despite widespread use, a complete understanding of the mechanism of action of general anesthetics has been lacking.
In a study using single-particle tracking photoactivation localization microscopy, researchers at the University of Queensland reported that the drugs do much more than induce sleep. In their paper in Cell Reports this week they demonstrate that the synaptic release machinery is also a target.
"We looked at the effects of propofol on synaptic release," said associate professor Bruno van Swinderen. "We know from previous research that general anesthetics including propofol act on sleep systems in the brain, much like a sleeping pill," he noted. "But our study found that propofol also disrupts presynaptic mechanisms, probably affecting communication between neurons across the entire brain in a systematic way that differs from just being asleep."
"We found that propofol restricts the movement of a key protein (syntaxin1A) required at the synapses of all neurons. This restriction leads to decreased communication between neurons in the brain," Ph.D. student Adekunle Bademosi added.
van Swinderen believes these findings could explain why people experience grogginess and disorientation after coming out of surgery. "We think that widespread disruption to synaptic connectivity—the brain's communication pathways—is what makes surgery possible, although effective anesthetics such as propofol do put you to sleep first," he said.
"The discovery has implications for people whose brain connectivity is vulnerable, for example in children whose brains are still developing or for people with Alzheimer's or Parkinson's disease.
"It has never been understood why general anesthesia is sometimes problematic for the very young and the old. This newly discovered mechanism may be a reason."
Image: A representation of thousands of tracked syntaxin1A molecules in a neuron exposed to propofol. Image courtesy of Bruno van Swinderen.