Neurosteroid Biosynthesis Regulates Sexually Dimorphic Fear and Aggressive Behavior in Mice

The neurosteroid allopregnanolone is a potent positive allosteric modulator of GABA action at GABAA receptors. Allopregnanolone is synthesized in the brain from progesterone by the sequential action of 5α-reductase type I (5α-RI) and 3α-hydroxysteroid dehydrogenase (3α-HSD). 5α-RI and 3α-HSD are co-expressed in cortical, hippocampal, and olfactory bulb glutamatergic neurons and in output neurons of the amygdala, thalamus, cerebellum, and striatum. Neither 5α-RI nor 3α-HSD mRNAs is expressed in glial cells or in cortical or hippocampal GABAergic interneurons. It is likely that allopregnanolone synthesized in principal output neurons locally modulates GABAA receptor function by reaching GABAA receptor intracellular sites through lateral membrane diffusion. This review will focus on the behavioral effects of allopregnanolone on mouse models that are related to a sexually dimorphic regulation of brain allopregnanolone biosynthesis. Animal models of psychiatric disorders, including socially isolated male mice or mice that receive a long-term treatment with anabolic androgenic steroids (AAS), show abnormal behaviors such as altered fear responses and aggression. In these animal models, the cortico-limbic mRNA expression of 5α-RI is regulated in a sexually dimorphic manner. Hence, in selected glutamatergic pyramidal neurons of the cortex, CA3, and basolateral amygdala and in granular cells of the dentate gyrus, mRNA expression of 5α-RI is decreased, which results in a downregulation of allopregnanolone content. In contrast, 5α-RI mRNA expression fails to change in the striatum medium spiny neurons and in the reticular thalamic nucleus neurons, which are GABAergic.By manipulating allopregnanolone levels in glutamatergic cortico-limbic neurons in opposite directions to improve [using the potent selective brain steroidogenic stimulant (SBSS) S-norfluoxetine] or induce (using the potent 5α-RI inhibitor SKF 105,111) behavioral deficits, respectively, we have established the fundamental role of cortico-limbic allopregnanolone levels in the sexually dimorphic regulation of aggression and fear. By selectively targeting allopregnanolone downregulation in glutamatergic cortico-limbic neurons, i.e., by improving the response of GABAA receptors to GABA, new therapeutics would offer appropriate and safe management of psychiatric conditions, including impulsive aggression, irritability, irrational fear, anxiety, posttraumatic stress disorders, and depression.