Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal - PubMed (original) (raw)

Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal

D G Rainnie et al. Science. 1994.

Erratum in

Abstract

Increased discharge activity of mesopontine cholinergic neurons participates in the production of electroencephalographic (EEG) arousal; such arousal diminishes as a function of the duration of prior wakefulness or of brain hyperthermia. Whole-cell and extracellular recordings in a brainstem slice show that mesopontine cholinergic neurons are under the tonic inhibitory control of endogenous adenosine, a neuromodulator released during brain metabolism. This inhibitory tone is mediated postsynaptically by an inwardly rectifying potassium conductance and by an inhibition of the hyperpolarization-activated current. These data provide a coupling mechanism linking neuronal control of EEG arousal with the effects of prior wakefulness, brain hyperthermia, and the use of the adenosine receptor blockers caffeine and theophylline.

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Figures

Fig. 1

Fig. 1

Endogenous AD exerts a tonic inhibition in the LDT and DBB, in vitro. (A) Spike frequency histogram of extracellularly recorded action potential firing in a neuron of the LDT. Superfusion with AD (100 μM) causes a marked reduction of firing frequency and CPT (10 μM) causes a prolonged increase in firing frequency. (B) In the DBB, application of CPT (10 μM) similarly increases firing rates, and subsequent exogenous AD decreased firing rates. (C) Application of 8-_p_-ST (50 μM) mimics the effect of CPT in an LDT neuron. (D) Whole-cell voltage-clamp recording of the response of a histochemically identified LDT cholinergic neuron to OPT application. _E_m, membrane potential. Digital subtraction of steady-state voltage-current relations obtained before and during OPT (10 μM) reveals a CPT-induced current with voltage and kinetic characteristics of _I_h. (Inset) Enhanced inward relaxation during CPT application. The relatively hyperpolarized reversal potential for _I_h may reflect a small additional presynaptic input evoked by CPT.

Fig. 2

Fig. 2

Exogenous AD application reduces an inwardly relaxing _I_h current in LDT neurons. (A) Current traces of an LDT neuron before and during AD application. Voltage step commands (−10 to −50 mV; 500 ms) from a holding potential of −60 mV reveal a slow inwardly relaxing current of increasing amplitude (upper traces). The presence of AD (20 μM) reduces the expression of the inward relaxation (lower traces). (B) A plot of the voltage-current relation determined for the inward relaxation before and during AD application. (Inset) The inward relaxation current (_I_relax) was calculated by subtraction of the instantaneous current (_I_i) from the steady-state current (_I_ss) for each of the current traces in (A).

Fig. 3

Fig. 3

Exogenous AD application evokes a membrane hyperpolarization mediated by activation of an inwardly rectifying K+ conductance in neurons of the LDT. (A) In a whole-cell current-clamp recording, AD evokes a membrane hyperpolarization and an associated decrease in membrane input resistance. (B) Current trace from another neuron voltage clamped at _V_h = −60 mV. Application of AD evokes an outward current and an associated increase in membrane conductance. Downward deflections in (A) and (B) reflect the voltage and current response to 100-pA, 20-mV hyperpolarizing step commands 200 ms in duration that were used to determine the resistance and conductance. (C) A plot of AD current as a function of membrane potential reveals AD activation of an inwardly rectifying K+ conductance. AD current was calculated by digital subtraction of the current evoked by “ramping” the neuron from −100 to −40 mV [see (B)] in control from that obtained during AD application. (D) AD chord conductance G as a function of membrane potential is well fit by a Boltzmann equation (dashed line) with a half-activation potential _V_1/2 of −85 mV and a slope factor of k = 9 [same neuron as in (C)].

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