New research published in the journal Anesthesiology provides fresh insights into how volatile anesthetics affect the central nervous system. Although anesthesia has been practiced for nearly 75 years, the precise cellular mechanisms driving anesthetic responses have remained ambiguous. Recent reports suggest mitochondria have a key role in the process, but prior research has only studied this connection in neurons. Now, researchers argue that astrocytes are also important, particularly when it comes to emergence from anesthesia.
To reach this conclusion, the team produced a novel knockout mouse lacking the mitochondrial complex I gene known as Ndufs4. In the model, gene knockout is induced only in astrocytes of adult animals – the other cell types comprising the central nervous system retain functional copes of the gene. The result is astrocyte-specific mitochondrial dysfunction.
To look at the role of this dysfunction in the anesthetic response, the researchers measured anesthetic sensitivity in both knockout mice and their wild-type counterparts. The mice were exposed to either isoflurane or halothane, and two different anesthetic endpoints were measured: loss of righting reflex and response to a tail clamp. These endpoints model different facets of the human anesthetic response: the response to tail clamp is mediated by the spinal cord with supraspinal modification, whereas the loss of righting reflex is likely mediated by interactions between the brainstem and thalamocortical pathways.
Interestingly, no differences were observed between mice for the induction concentrations of either anesthetic. But a lower emergence concentration was required for mice with NDUFS4-deficient astrocytes for both anesthetics and both endpoints. These results suggest that an astrocyte-specific mechanism is necessary for regaining consciousness.
One explanation is that inhibiting astrocyte mitochondria blocks key signaling events or metabolic pathways in these cells. This could make it tough for the cells to regain excitatory synaptic function––until anesthetic concentrations are lowered enough for mitochondria to become active again.
Translating these findings to the clinical setting remains tricky. The researchers aren’t sure exactly how Ndufs4 knockout impacts astrocytic function. It’s also not clear whether loss of the gene affects other critical pathways in the brain. But the results do strongly support the critical role of astrocytes in restoring consciousness after anesthesia.