Pentobarbitone modulates calcium transients in axons and synaptic boutons of hippocampal CA1 neurons

Abstract

1 Although barbiturates, like other general anaesthetics, depress excitatory synaptic transmission in the central nervous system (CNS), the underlying cellular mechanisms remain unresolved. They may increase the likelihood that an action potential will fail to invade every branch of the axonal arbour, thereby decreasing the synaptic drive to the postsynaptic neurons. Alternatively, they may inhibit calcium entry into the presynaptic terminals, thus reducing transmitter release. 2 To resolve these issues, we have used two-photon microscopy to monitor calcium transients evoked by action potentials in axons, axonal varicosities (synaptic boutons) and fine axon collaterals of hippocampal CA1 neurons. 3 Pentobarbitone (75 -300 mM) did not block the invasion of the axonal arbour or the synaptic boutons, but it did reduce the amplitude of the calcium transients recorded from the axons in a concentration-dependent manner. At 150 mM, pentobarbitone reduced the transients to 7874% of the control. 4 Pentobarbitone depressed the calcium transients recorded from the synaptic boutons in a concentration-dependent manner. When 150 mM pentobarbitone was applied, the calcium transients recorded from the boutons were 5373% of the control. This concentration of pentobarbitone also reduced the amplitude and frequency of the spontaneous excitatory postsynaptic potentials to 5474 and 42717% of the control, respectively. 5 The local anaesthetic procaine (500 mM) had no significant effect on action potential invasion of axon collaterals, even though it reduced the action potential amplitude by 25%. 6 This data are consistent with the notion that the pentobarbitone-induced depression of presynaptic calcium transients contributes to its depressant effect on excitatory synaptic transmission in the CNS.

Pentobarbital inhibition of human recombinant α1A P/Q‐type voltage‐gated calcium channels involves slow, open channel block

“…CNS depression arises from their well‐known enhancement of inhibitory post‐synaptic Cl ‐ currents carried by GABA A receptors (Evans, 1979; Mathers and Barker, 1980; Olsen, 1988; Macdonald et al . 1989), and also by inhibition of excitatory pre‐synaptic neurotransmitter release (Brooks and Eckert, 1947; Weakly, 1969; Richards, 1972; Baudoux et al ., 2003) involving reduced Ca 2+ entry into the pre‐synaptic nerve terminal (Morgan and Bryant, 1977; Leslie et al . 1980; Baudoux et al ., 2003).…”

Effects of propofol and pentobarbital on calcium concentration in presynaptic boutons on a rat hippocampal neuron

“…pre increase in the presynaptic boutons [16,17] and depresses excitatory synaptic transmission in the CNS [18]. In these reports, the inhibitory [13,14] and 150-300 lM [17,18], respectively. Pentobarbital concentration of 200 lM was sufficient to inhibit depolarization-induced secretion by 30-50% [18].…”

“…-evoked glutamate release from rat cerebrocortical slices by mediating activation of GABA A receptors [13]. However, it has also been suggested that presynaptic GABA A receptors are not implicated in depressant actions of IV anesthetic agents in the presynaptic boutons [16,17]. Furthermore, it has been reported that GABA A receptors also reduce neurotransmitter release by another mechanism that does not affect Ca 2?…”

“…Pentobarbital inhibits voltage-sensitive calcium (Ca 2? ) channels [16] and reduces the amplitude of calcium transients in presynaptic terminals (boutons) [17]. As a consequence, this agent depresses excitatory synaptic transmission in the CNS [18].…”

Anesthetic Agent-Specific Effects on Synaptic Inhibition

“…Thus, pentobarbital depressed EPSP responses by both enhancing dendritic inhibition, as well as by a presynaptic action to reduce glutamate release as previously reported. (36) …”