Pleiotropic endophenotypic and phenotype effects of GABAergic neurosteroid synthesis deficiency in posttraumatic stress disorder

PTSD is associated with deficits in synthesis of progesterone metabolites such as allopregnanolone and pregnanolone that potently facilitate gamma-amino-butyric acid (GABA) effects at GABA_A receptors. These neurosteroids modulate neuronal firing rate, regional brain connectivity, and activation of amygdala-mediated autonomic nervous system, hypothalamic–pituitary–adrenal axis, and behavioral reactions to unconditioned and conditioned threat. They also play critical roles in learning and memory processes such as extinction and extinction retention and inhibit toll-like receptor activation of intracellular pro-inflammatory pathways. Deficient synthesis of these neurosteroids thus may contribute to individually variable PTSD clinical phenotypes encompassing symptom severity, capacity for PTSD recovery, and vulnerability to common PTSD-comorbidities such as major depression, chronic pain, alcohol and nicotine dependence, cardiovascular disease, metabolic syndrome, reproductive disorders, and autoimmune conditions.