Targeting emotional brain circuits with neurosteroid modulators of GABAA receptor function.

摘要

The neurosteroid (NS) allopregnanolone (ALLO), a potent positive allosteric modulator of the action of GABA at GABAA receptors (GABA A-Rs), is synthesized in the brain by the sequential action of two enzymes: 5alpha-reductase type I (5alpha-RI), which transforms progesterone into 5alpha-dihydroprogesterone (5alpha-DHP) and 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD), which converts 5alpha-DHP into ALLO. The overarching hypothesis of my thesis work is that protracted (3--4 weeks) social isolation (Si) in male mice elicits a down-regulation of 5alpha-RI expression and a decrease in the expression of ALLO levels in specific neurons of the cortico-hippocampal-amygdaloid neuronal circuits.;In order to address the hypothesis, first I evaluated 5alpha-RI and 3alpha-HSD mRNA expression level in mouse brain by using in situ hybridization combined with immunohistochemistry. In the cortex, hippocampus, amygdala, thalamus, and olfactory bulb, these enzymes are colocalized in principal glutamatergic output neurons but are not detectable in GABAergic interneurons. Neither 5alpha-RI nor 3alpha-HSD mRNAs are expressed in glial cells. Taken together, these data suggest that ALLO, which can be synthesized in principal output neurons, modulate GABA action at GABAA-Rs, either with an autrocrine or a paracrine mechanism or by reaching GABA A-R intracellular sites through lateral membrane diffusion.;The second objective was to examine whether a reduction in 5alpha-RI and consequently of ALLO expression in the glutamatergic neurons of the frontal cortex, hippocampus, and amygdala by down-regulating GABAergic neurotransmission impair the function of cortico-hippocampal-amygdaloid circuits and explain the aggression observed in socially isolated mice.;In adult male mice following a period of protracted Si, ALLO biosynthesis and 5alpha-RI mRNA expression are specifically down-regulated in glutamatergic neurons that converge on the amygdala from cortical and hippocampal regions. Importantly, 3alpha-HSD mRNA expression was unchanged. The down-regulation of 5alpha-RI and ALLO may account for the appearance of behavioral disorders such as aggression, anxiety, and cognitive dysfunction in SI mice.