Isoflurane impairs learning and hippocampal long-term potentiation via the saturation of synaptic plasticity.
BACKGROUND
General anesthesia induces long-lasting cognitive and learning deficits. However, the underlying mechanism remains unknown. The GluA1 subunit of AMPAR is a key molecule for learning and synaptic plasticity, which requires trafficking of GluA1-containing AMPARs into the synapse.


METHODS
Adult male rats were exposed to 1.8% isoflurane for 2 h and subjected to an inhibitory avoidance task, which is a hippocampus-dependent contextual fear learning paradigm (n = 16 to 39). The in vitro extracellular field potential of hippocampal synapses between the Schaffer collateral and the CA1 was evaluated using a multielectrode recorder (n = 6 per group). GluA1 expression in the synaptoneurosome was assessed using Western blotting (n = 5 to 8). The ubiquitination level of GluA1 was evaluated using immunoprecipitation and Western blotting (n = 7 per group).


RESULTS
Seven days after exposure to 1.8% isoflurane for 2 h (Iso1.8), the inhibitory avoidance learning (control vs. Iso1.8; 294 ± 34 vs. 138 ± 28, the mean ± SEM [%]; P = 0.002) and long-term potentiation (125.7 ± 6.1 vs. 105.7 ± 3.3; P < 0.001) were impaired. Iso1.8 also temporarily increased GluA1 in the synaptoneurosomes (100 ± 9.7 vs. 138.9 ± 8.9; P = 0.012) and reduced the GluA1 ubiquitination, a main degradation pathway of GluA1 (100 ± 8.7 vs. 71.1 ± 6.1; P = 0.014).


CONCLUSIONS
Isoflurane impairs hippocampal learning and modulates synaptic plasticity in the postanesthetic period. Increased GluA1 may reduce synaptic capacity for additional GluA1-containing AMPARs trafficking.
From the Department of Anesthesiology and Critical Care Medicine (K.U., T.M., Ta.M., Y.K., G.I., T.G.), Department of Physiology (T.M., T.T.), and Department of Biostatistics and Epidemiology (M.T.), Yokohama City University Graduate School of Medicine, Yokohama, Japan; and Department of Anesthesiology (Y.K.), Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Kazuhiro
K
Uchimoto
Tomoyuki
T
Miyazaki
Yoshinori
Y
Kamiya
Takahiro
T
Mihara
Yukihide
Y
Koyama
Masataka
M
Taguri
Gaku
G
Inagawa
Takuya
T
Takahashi
Takahisa
T
Goto
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001784:Blood Gas Analysis; D015153:Blotting, Western; D003071:Cognition / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects*; D047468:Immunoprecipitation; D007530:Isoflurane / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D008839:Microelectrodes; D009473:Neuronal Plasticity / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000187:drug effects*; D054875:Ubiquitination / Q000187:drug effects
D018685:Anesthetics, Inhalation; D007530:Isoflurane; D018091:Receptors, AMPA