Abstract
General anesthetics disrupt brain processes involved in consciousness by altering synaptic patterns of excitation and inhibition. In the cerebral cortex and hippocampus, GABAergic inhibition is largely mediated by inhibitory interneurons, a heterogeneous group of specialized neuronal subtypes that form characteristic microcircuits with excitatory neurons. Distinct interneuron subtypes regulate specific excitatory neuron networks during normal behavior, but how these interneuron subtypes are affected by general anesthetics is unclear. This narrative review summarizes current principles of the synaptic architecture of cortical and interneuron subtypes, their contributions to different forms of inhibition, and their roles in distinct neuronal microcircuits. The molecular and cellular targets in these circuits that are sensitive to anesthetics are reviewed in the context of how anesthetics impact interneuron function in a subtype-specific manner. The implications of this functional interneuron diversity for mechanisms of anesthesia are discussed, as are their implications for anesthetic-induced changes in neural plasticity and overall brain function.
Highlights
The mechanistic understanding of general anesthesia has seen substantial recent progress, but there is a conceptual gap between the molecular pharmacology of anesthetic targets and the network level changes in the anesthetized central nervous system (CNS)
We describe the architecture for interneuron specialization, including their heterogeneous expression of known molecular targets for various anesthetics, and discuss evidence of interneuron subtype-specific anesthetic sensitivities determined by differential expression of these anesthetic targets
Isoflurane, ketamine, and urethane anesthesia all elicit short-term changes in evoked inhibitory responses, suggesting plasticity of inhibitory synapses, as normal interneuronexcitatory neuron connections are altered during anesthesia (Taub et al, 2013)
Summary
The mechanistic understanding of general anesthesia has seen substantial recent progress, but there is a conceptual gap between the molecular pharmacology of anesthetic targets and the network level changes in the anesthetized central nervous system (CNS). Interneuron subpopulations include multiple subtypes (Figure 1) with characteristic phenotypes for modulation of excitability, action potential (AP) firing behavior, synaptic connectivity, and network-level functions. About 20% of hippocampal and 15% of cortical interneurons express VIP and/or calretinin (CR) and selectively target other interneurons This circuit role is thought to disinhibit local excitatory cells by creating holes in the ‘‘blanket of inhibition’’, and/or modulate spatiotemporal patterns of inhibition and tune the excitatory cell input/output firing relationship (Karnani et al, 2014). Guet-McCreight and colleagues reviewed recent studies into hippocampal and cortical VIP+ and CR+ interneuron-containing circuits, with special comparisons for distinct cortical regions with comparable actions (Guet-McCreight et al, 2020) Across these subregions, VIP/CR+ disinhibition commonly serves to control the integration of input to excitatory neurons and to control synaptic plasticity. Modeling studies of anesthetized human EEG data could be facilitated by incorporating elements that account for interneuron neurophysiological and pharmacological diversity
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