TY - JOUR
T1 - Frequency-dependent block of excitatory neurotransmission by isoflurane via dual presynaptic mechanisms
AU - Wang, Han Ying
AU - Eguchi, Kohgaku
AU - Yamashita, Takayuki
AU - Takahashi, Tomoyuki
N1 - Publisher Copyright:
Copyright © 2020 Wang et al.
PY - 2020/5/20
Y1 - 2020/5/20
N2 - Volatile anesthetics are widely used for surgery, but neuronal mechanisms of anesthesia remain unidentified. At the calyx of Held in brainstem slices from rats of either sex, isoflurane at clinical doses attenuated EPSCs by decreasing the release probability and the number of readily releasable vesicles. In presynaptic recordings of Ca21 currents and exocytic capacitance changes, isoflurane attenuated exocytosis by inhibiting Ca21 currents evoked by a short presynaptic depolarization, whereas it inhibited exocytosis evoked by a prolonged depolarization via directly blocking exocytic machinery downstream of Ca21 influx. Since the length of presynaptic depolarization can simulate the frequency of synaptic inputs, isoflurane anesthesia is likely mediated by distinct dual mechanisms, depending on input frequencies. In simultaneous presynaptic and postsynaptic action potential recordings, isoflurane impaired the fidelity of repetitive spike transmission, more strongly at higher frequencies. Furthermore, in the cerebrum of adult mice, isoflurane inhibited monosynaptic corticocortical spike transmission, preferentially at a higher frequency. We conclude that dual presynaptic mechanisms operate for the anesthetic action of isoflurane, of which direct inhibition of exocytic machinery plays a low-pass filtering role in spike transmission at central excitatory synapses.
AB - Volatile anesthetics are widely used for surgery, but neuronal mechanisms of anesthesia remain unidentified. At the calyx of Held in brainstem slices from rats of either sex, isoflurane at clinical doses attenuated EPSCs by decreasing the release probability and the number of readily releasable vesicles. In presynaptic recordings of Ca21 currents and exocytic capacitance changes, isoflurane attenuated exocytosis by inhibiting Ca21 currents evoked by a short presynaptic depolarization, whereas it inhibited exocytosis evoked by a prolonged depolarization via directly blocking exocytic machinery downstream of Ca21 influx. Since the length of presynaptic depolarization can simulate the frequency of synaptic inputs, isoflurane anesthesia is likely mediated by distinct dual mechanisms, depending on input frequencies. In simultaneous presynaptic and postsynaptic action potential recordings, isoflurane impaired the fidelity of repetitive spike transmission, more strongly at higher frequencies. Furthermore, in the cerebrum of adult mice, isoflurane inhibited monosynaptic corticocortical spike transmission, preferentially at a higher frequency. We conclude that dual presynaptic mechanisms operate for the anesthetic action of isoflurane, of which direct inhibition of exocytic machinery plays a low-pass filtering role in spike transmission at central excitatory synapses.
KW - Calyx of Held
KW - Cerebral cortical synapse
KW - Exocytic capacitance change
KW - Frequency-dependent inhibition
KW - Isoflurane
KW - Presynaptic Ca currents
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U2 - 10.1523/JNEUROSCI.2946-19.2020
DO - 10.1523/JNEUROSCI.2946-19.2020
M3 - Article
C2 - 32327530
AN - SCOPUS:85085265868
SN - 0270-6474
VL - 40
SP - 4103
EP - 4115
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 21
ER -