Hippocampal astrocyte dysfunction contributes to etomidate-induced long-lasting synaptic inhibition

Hippocampal microglial activation triggers a neurotoxic-specific astrocyte response and mediates etomidate-induced long-term synaptic inhibition

“…In addition, microglial elimination or inhibition suppressed hippocampal inflammatory responses and reduced the levels of cytokines such as IL-6, IL-1β, and TNFα following anesthesia and other pathological conditions [17,33,34]. Moreover, the level of inositol 1,4,5-triphosphate type 2 receptor-dependent calcium was reduced in astrocytes, even after a sedative dose of anesthetic [35], and long-term inhibition of astrocytes is consistent with synaptic suppression and cognitive deficiencies [24]. Interestingly, in this study, nonspecific microglial activation occurred during the early pathological stage, together with synaptic inhibition and cognitive dysfunction, which were slightly alleviated during the late pathological stage, in an aged (18-monthold) PND mice model.…”

“…Postsynaptic GABAA-R channels trigger fast and transient phasic inhibitory currents that produce amnesia, unconsciousness, and immobility, whereas extrasynaptic GABAA-R channels induce slow and persistent tonic inhibitory currents that produce undesirable effects, such as delirium and cognitive deficiencies [10]. However, many unanswered questions remain, such as (i) why does extrasynaptic GABAA-R induced longterm synaptic inhibition require astrocyte activation [14]; (ii) why are etomidate-generated GABAA-R tonic inhibitory currents alone insufficient to cause amnesia, and what other components are involved [28]; (iii) what roles do microglial and astrocyte activation play in regulating synaptic inhibition during and after anesthesia [24,29]; (iv) is there crosstalk between the microglial and astrocyte pathways; and (v) can microglial or astrocytic inhibition alone rescue long-term synaptic inhibition and cognitive dysfunction?…”

“…Designer receptors exclusively activated by designer drugs (DREADDs) application were performed as previous study described [24]. Chemogenetical virus AAV2/ 9-Gfap-hM4D(Gi)-mCherry-WPRE-pA (titer, 1.72 × 1013 vg/mL) was purchased from HANBIO Technology (Shanghai, China) and injected into the hippocampus of mice under anesthetic state which is induced by isoflurane (1.3%) for as much time as it takes and fixed on a stereotaxic apparatus (RWD, Shenzhen, China).…”

“…Etomidate administration results in long-term synaptic inhibition and cognitive dysfunction in older mice [24]. Therefore, we also assessed cognitive function and glial responses 3 weeks after the injections ( Fig.…”

“…Astrocyte dysfunction causes long-term synaptic inhibition and cognitive impairments [24]. However, it is unclear whether microglial-activation-induced inflammatory responses can induce these impairments without triggering A1-specific astrocyte responses.…”