Background: Propofol produces memory impairment at concentrations well below those abolishing consciousness. Episodic memory, mediated by the hippocampus, is most sensitive. Two potentially overlapping scenarios may explain how γ-aminobutyric acid receptor type A (GABAA) potentiation by propofol disrupts episodic memory—the first mediated by shifting the balance from excitation to inhibition while the second involves disruption of rhythmic oscillations. We use a hippocampal network model to explore these scenarios. The basis for these experiments is the proposal that the brain represents memories as groups of anatomically dispersed strongly connected neurons.
Methods: A neuronal network with connections modified by synaptic plasticity was exposed to patterned stimuli, after which spiking output demonstrated evidence of stimulus-related neuronal group development analogous to memory formation. The effect of GABAA potentiation on this memory model was studied in 100 unique networks.
Results: GABAA potentiation consistent with moderate propofol effects reduced neuronal group size formed in response to a patterned stimulus by around 70%. Concurrently, accuracy of a Bayesian classifier in identifying learned patterns in the network output was reduced. Greater potentiation led to near total failure of group formation. Theta rhythm variations had no effect on group size or classifier accuracy.
Conclusions: Memory formation is widely thought to depend on changes in neuronal connection strengths during learning that enable neuronal groups to respond with greater facility to familiar stimuli. This experiment suggests the ability to form such groups is sensitive to alteration in the balance between excitation and inhibition such as that resulting from administration of a γ-aminobutyric acid–mediated anesthetic agent.
Episodic memory encoding is dependent upon the hippocampus; repetitive stimuli strengthen synaptic connections and lead to the development of groups of neurons with synchronous activity called polychronous groups.
The hippocampal formation has multiple connections, including those with the entorhinal cortex and medial septum. Interactions within these connections lead to synchronized oscillations, primarily theta, that can be detected electroencephalographically.
Although propofol and other enhancers of γ-aminobutyric acid receptor type A activity produce amnesia, the precise mechanisms by which they interfere with memory-encoding processes such as synaptic plasticity-induced polychronous neuronal group formation versus theta oscillations are not clear.
In a computational model of the hippocampus, propofol reduced polychronous group size in a dose-dependent manner. By contrast, modulation of theta oscillations did not affect group size.
The results suggest formation of polychronous groups of neurons is more sensitive to the effect of propofol on the balance between excitation and inhibition than on theta oscillations.
Kingsley P. Storer, George N. Reeke; γ-Aminobutyric Acid Type A Receptor Potentiation Inhibits Learning in a Computational Network Model. Anesthesiology 2018;129(1):106-117. doi: https://doi.org/10.1097/ALN.0000000000002230.
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