Regulation of somatostatin synthesis by GABAA receptor stimulation in mouse brain

Neuroanatomical data have documented the existence of synaptic contacts between gamma-aminobutyric acid (GABA) terminals and periventricular hypothalamic somatostatin (SRIF) neurons. In other brain regions, like the cortex or hippocampus, GABA and SRIF are colocalized in short interneurons. These observations suggest that GABA modulates SRIF neuronal activity. In order to test this hypothesis, we studied the effects of the in vivo stimulation of the GABAA receptor (muscimol, 0.75 mg/kg + diazepam, 2.5 mg/kg) on SRIF content and preproSRIF mRNA levels, in mouse brain. Chronic (7 days), but not acute, treatment induced a 38% decrease in hypothalamic SRIF content (as estimated by RIA), a 20% decrease in cortex and no effect in the striatum. The decrease in hypothalamic and cortical SRIF levels lasted until 24 h after cessation of the treatment. In the hypothalamus, prosomatostatin mRNA levels were estimated by Northern blot analysis using a 32P-labeled 45-mere oligoprobe. ProSR1F mRNA hypothalamic levels were equally (48%) decreased by the acute and chronic treatments and remained lower than controls 48 h after the last injection. Quantitative in situ hybridization was used to examine the regional distribution of GABA-induced acute inhibition of proSR1F mRNA densities, using the same oligomere labeled with 35S. ProSR1F mRNA levels were decreased by 35% in the periventricular hypothalamic nucleus. In contrast, no significant modification was observed in cortex, striatum and hilus of the dentate gyrus of the dorsal hippocampus. The present data demonstrate a regionally selective inhibitory action of GABA, mediated by GABAA receptors stimulation, on the biosynthetic mechanisms of the long projecting neuroendocrine SRIF neurons of the anterior periventricular nucleus of the hypothalamus.