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Volume 2 Supplement 1

Neural Control of Breathing

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On synchronizing pH-sensitive subthreshold oscillations of membrane potential in locus coeruleus (LC) neurones

The LC is composed for the most part (ca. 90%) of pH-chemosensitive neurones which under in vitro conditions show a strong tendency to synchronize their discharge. The object of this study was to explore some of the mechanisms involved in such synchronization. In neonatal LC neurones the most prominent feature contributing to spike synchronization is a low frequency subthreshold rhythmic oscillation (SRO) of membrane potential which has been attributed to gap junction-mediated electrical coupling. In the present experiments we took advantage of the fact that in the en bloc isolated neonatal brainstem-spinal cord LC neurones receive a respiratory-phased innervation [1]. It was thus possible to examine the influence on the electrically coupled network of a naturally occurring rhythmic synaptic input. In simultaneous whole cell and extracellular recordings from LC neurones in this preparation there was a strong tendency towards the synchronous occurrence of spikes and, when examined in paired whole cell recordings, it was apparent that this was due to strong synchronization of their SRO. Under conditions of intact chemical synaptic transmission, current injection into one neurone failed to influence membrane potential, SRO frequency or the timing of spike discharge in the other neurones.

The timing of the respiratory cycle, simultaneously recorded as the efferent discharge on a phrenic root, influenced the timing of the SRO: the occurrence of a phrenic burst triggered a wave of depolarization and the insertion of one or a small number of extra spikes; this was followed by a delay to the onset of the next spontaneously occurring oscillation. Addition of QX314 (4 mM) to the pipette solution to block voltage-gated Na+ conductances suppressed the discharge of large, rapid spikes and revealed that the underlying SRO was composed of a slow depolarizing wave with superimposed small depolarizing transients. These transients, which we have previously shown to be blocked by Cd2+ and which are therefore presumably Ca2+ spikes, were synchronized with the full sized extracellularly recorded spikes of a second LC neurone. The effect of the respiratory-phased synaptically-mediated input was, first, to trigger a short sequence of synchronized Ca2+ spikes throughout the network, and then for a short period to inhibit the network, ie, to delay the next SRO cycle, via an α2-adrenoceptor-mediated mechanism. This last suggests that the inhibition depends on noradrenaline released either by LC neurones themselves or by respiratory-phased afferent input. Raising the CO2 concentration (2–10%) eliminates the inhibition and increases SRO frequency on average by a factor of 2 (equivalent to a spike frequency increase of about 50%) [1].

Following partial or complete replacement of extracellular Ca2+ with Ba2+, and in the presence of TTX, the synchronized SRO was transformed into a large amplitude oscillation. The frequency of this rhythm was partly set by a ramp-like growth of depolarization which initiated each cycle of oscillation, and which was sensitive to pH, the frequency of oscillation increasing by about 30% when the CO2 concentration was raised from 2 to 10%.

These observations suggest that synchronizing mechanisms within this network normally include both chemical synaptic input and electrical coupling of a pH-sensitive Ca2+-dependent rhythm (SRO), which does not itself depend on such input.


  1. Oyamada Y, Ballantyne D, Mückenhoff K, Scheid P: Respiration-modulated membrane potential and chemosensitivity of locus coeruleus neurones in the in vitro brainstem-spinal cord of the enonatal rat. J Physiol. 1998, 513: 381-398. 10.1111/j.1469-7793.1998.381bb.x.

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Andrzejewski, M., Ballantyne, D., Mückenhoff, K. et al. On synchronizing pH-sensitive subthreshold oscillations of membrane potential in locus coeruleus (LC) neurones. Respir Res 2 (Suppl 1), 6.2 (2001).

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