GABAB receptor-mediated tonic inhibition regulates the spontaneous firing of locus coeruleus neurons in developing rats and in citalopram-treated rats.

Abstract

Noradrenaline (NA)-releasing neurons in the locus coeruleus (LC) provide NA to the forebrain and play important roles in regulating many brain functions. LC neurons are subject to tonic inhibition mediated by GABAB receptors (GABAB Rs) and that the extent of the effect varies with ambient GABA levels. GABAB R-mediated tonic inhibition can effectively tune the spontaneous firing rate (SFR) of LC neurons; it is developmentally regulated and is responsible for maintaining a constant SFR of LC neurons during development. In male, but not female rats, chronic perinatal treatment with citalopram, a selective serotonin reuptake inhibitor, results in downregulation of GABAB R-mediated tonic inhibition of LC neurons that partially accounts for increased SFR in male, but not female, rats receiving such treatment. Our results show that GABAB R-mediated tonic inhibition could be an important player in the development of normal and abnormal behaviours/brain functions associated with the LC-NA system. Noradrenaline (NA)-releasing neurons in the locus coeruleus (LC) provide NA to the forebrain. Their activity is believed to be a key factor regulating the wakefulness/arousal level of the brain. In this study, we found that the activity of NA-releasing neurons in the LC (LC neurons) was subject to γ-aminobutyric acid (GABA) tonic inhibition through GABAB receptors (GABAB Rs), but not GABAA receptors. The intensity of GABAB R tonic inhibition was found to depend on ambient GABA levels, as it was dramatically increased by blockade of GABA reuptake. It also varied with the function of GABAB Rs. The GABAB R activity on LC neurons was found to increase with postnatal age up to postnatal days 8-10, resulting in increased tonic inhibition. Interestingly, there was no significant difference in the spontaneous activity of LC neurons at different postnatal ages unless GABAB R tonic inhibition was blocked. These results show that, during postnatal development, there is a continuous increase in GABAB R tonic inhibition that maintains the activity of LC neurons at a proper level. In male, but not female, rats, chronic perinatal treatment with citalopram, a selective serotonin reuptake inhibitor, reduced GABAB R activity and tonic inhibition, which might result in the significantly higher spontaneous activity of LC neurons seen in these animals. In conclusion, our results show that GABAB R-mediated tonic inhibition has a direct impact on the spontaneous activity of LC neurons and that the extent of the effect varies with ambient GABA levels and functionality of GABAB R signalling.