Steroid hormone fluctuations and GABA(A)R plasticity.
Conditions of changing steroid hormone levels are a particularly vulnerable time for the manifestation of neurological disorders, including catamenial epilepsy, premenstrual syndrome (PMS), and postpartum depression. The pathophysiology of these disorders may be related to changes in neurosteroid levels, which can dramatically impact neuronal excitability. Robust changes in neurosteroid levels, such as those that occur following stress, over the ovarian cycle, and throughout pregnancy, profoundly alter GABAA receptor (GABAAR) structure and function and underlie the associated changes in neuronal excitability. A moderate and brief exposure to elevated neurosteroids, such as those that occur over the ovarian cycle and following an acute stressful episode, result in a decrease in GABAAR gamma2 subunit expression and an increase in GABAAR delta subunit expression. These changes are accompanied by a decrease in seizure susceptibility and decreased anxiety-like behavior in mice, demonstrating altered neuronal excitability associated with changes in the receptor composition. More robust changes in steroid hormone levels, such as those that occur throughout pregnancy, result in a decrease in both GABAAR gamma2 and delta subunit expression and are associated with an increase in neuronal excitability evident from the shift in the input-output relationship. Alterations in GABAAR subunit composition may represent a homeostatic mechanism to maintain an ideal level of inhibition in the face of fluctuating neurosteroid levels. Neurosteroids potentiate the effects of GABA on GABAARs, particularly those containing the delta subunit, and reorganization of these receptors may be necessary to prevent sedation and/or anaesthesia in the face of high levels of neurosteroids or to prevent hyperexcitability in the absence of these compounds. Alterations in GABAARs under conditions of altered steroid hormone levels result in measurable changes in neuronal excitability and dysregulation of GABAARs may play a role in steroid hormone-associated neurological disorders.
Maguire
Jamie
J
Department of Neurology, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Mody
Istvan
I
D000818:Animals; D001921:Brain / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008597:Menstrual Cycle / Q000378:metabolism; D051379:Mice; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism* / Q000502:physiology; D011247:Pregnancy; D011963:Receptors, GABA-A / Q000378:metabolism* / Q000502:physiology*; D012640:Seizures / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology
C546279:GABRG2 protein, human; C546280:Gabrg2 protein, mouse; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A