For some drugs, including diazepam and etomidate, there is now good evidence that their ability to induce amnesia arises by way of GABAA
receptor modulation. In the case of etomidate, which critically depends on a5 subunit modulation, this may well occur primarily within the hippocampus itself.20,49,50
Other drugs, such as inhaled anesthetics, may work, at least in part, by this mechanism as well. If so, precisely how does receptor modulation translate to memory impairment?
There are two possible scenarios, which we will term “static” and “dynamic”. For the “static” scenario, the ability of repetitive stimuli (such as a 100 Hz stimulus train) to elicit synaptic plasticity may be suppressed by tilting the balance of synaptic input away from depolarization (excitation) and toward hyperpolarization (inhibition), thus preventing activation of NMDA receptors, calcium entry, and the ensuing cascades that result in LTP. In this regard, the characteristics of GABAA,slow inhibitory postsynaptic currents (IPSCs) are well-suited for this role. Like excitatory synapses, they are localized to the dendrites, and like NMDA receptors, they exhibit a long-lasting conductance. Alternatively, tonic inhibitory influences, which resist depolarization and are sensitive to low drug concentrations, and fast somatic inhibitory synapses, which prevent action potential generation and backpropagation, may also contribute. Perhaps the different mechanisms come into play under different protocols or learning paradigms.
The “dynamic” scenario invokes a more indirect anesthetic action. Since the orchestration of activity by endogenous rhythms in the hippocampus is thought to be essential to its ability to learn and recall activity patterns, might anesthetic-induced amnesia arise from a disruption of some critical aspect of timing required for proper mnemonic function? The type of plasticity an incoming signal elicits in the hippocampus depends on the phase of the θ-oscillation that the signal encounters.51,52
Hence, a change in θ-frequency without adjustment of the incoming signalling might interfere with plastic changes underlying memory formation – either preventing its initiation or rendering it too short-lived to support long-term memory storage. Hippocampal interactions with the prefrontal cortex, another important memory-related structure, are also coordinated by the θ-rhythm,53,54
with actual information transfer possibly carried by SW-R that require synchronization with cortical rhythms to lay down or reinforce memory traces.46
Disruption of this fine-tuned cross-frequency dialogue between the hippocampus and other parts of the brain involved in memory formation, consolidation, and storage degrades mnemonic function.55,56
The little evidence that exists to date indicates that anesthetics do not completely eliminate oscillations. However, subtle forms of interference, for example, through changes in θ-frequency,57
θ-power, θ-γ-nesting, SW-R etc., may all contribute to amnesia via anesthetic actions on a variety of molecular targets.