Frequency-Dependent Block of Excitatory Neurotransmission by Isoflurane via Dual Presynaptic Mechanisms.
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 Ca2+ currents and exocytic capacitance changes, isoflurane attenuated exocytosis by inhibiting Ca2+ currents evoked by a short presynaptic depolarization, whereas it inhibited exocytosis evoked by a prolonged depolarization via directly blocking exocytic machinery downstream of Ca2+ 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.SIGNIFICANCE STATEMENT Synaptic mechanisms of general anesthesia remain unidentified. In rat brainstem slices, isoflurane inhibits excitatory transmitter release by blocking presynaptic Ca2+ channels and exocytic machinery, with the latter mechanism predominating in its inhibitory effect on high-frequency transmission. Both in slice and in vivo, isoflurane preferentially inhibits spike transmission induced by high-frequency presynaptic inputs. This low-pass filtering action of isoflurane likely plays a significant role in general anesthesia.
['Wang|Han-Ying|HY|0000-0002-3021-7134', 'Eguchi|Kohgaku|K|0000-0002-6170-2546', 'Yamashita|Takayuki|T|0000-0002-1849-9837', 'Takahashi|Tomoyuki|T|0000-0002-8771-7666']
D018685:Anesthetics, Inhalation D000818:Animals D001933:Brain Stem D019706:Excitatory Postsynaptic Potentials D005089:Exocytosis D005260:Female D007530:Isoflurane D008297:Male D051379:Mice D009474:Neurons D018408:Patch-Clamp Techniques D017729:Presynaptic Terminals D051381:Rats D017208:Rats, Wistar D009435:Synaptic Transmission
isoflurane calyx of Held exocytic capacitance change cerebral cortical synapse frequency-dependent inhibition presynaptic Ca2+ currents