GABAergic Control of the Body’s Stress Response
GABAA receptors (GABAARs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS) and are dynamically regulated by a number of pathological (eg epilepsy) and physiological (eg pregnancy) conditions. We are investigating the GABAergic control of the body’s stress response. Stress is a trigger for numerous neurological and neuropsychiatric disorders, such as epilepsy, anxiety disorders, and depression. GABAergic inhibition controls the activity of the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the body’s response to stress. Our goal is to understand the role of the GABAergic control of the HPA axis in neurological and neuropsychiatric diseases.
GABAergic Regulation of the HPA Axis in Postpartum Depression
Nearly 20% of mothers suffer from postpartum depression, however, research into the pathophysiology of postpartum depression has been largely impeded by the lack of useful animal models of such a complex disorder. Our group proposes to elucidate the mechanisms underlying postpartum depression-like using a novel mouse model exhibiting postpartum depression-like behavior. We are testing the novel hypothesis that deficits in GABAergic regulation of corticotropin-releasing hormone (CRH) neurons results in dysregulation of the HPA axis that, in turn, leads to abnormal postpartum behaviors.
Figure 1. Downregulation of the GABAAR δ subunit during pregnancy. Immunohistochemical analysis reveals a decrease in GABAAR δ subunit expression in slices from pregnant mice (day 18) compared to virgin mice. The lack of GABAAR δ subunit immunoreactivity in the Gabrd-/- mice confirms the specificity of these findings.
GABAergic Control of the HPA Axis in Anxiety and Depression in Aging
We are testing the hypothesis that GABAergic dysregulation of the HPA axis underlies mood disorders associated with aging and, thereby, identify a potential therapeutic target for the treatment of mood disorders in the elderly. Mood disorders unrelated to aging, such as major depression, are associated with hyperactivity of the HPA axis and stress triggers both anxiety and depression, implicating the HPA axis in the pathophysiology of these disorders. Further, alterations in CRH signaling have been associated specifically with depression in the elderly. The HPA axis is controlled by CRH neurons in the paraventricular nucleus (PVN) and GABAergic inhibition regulates the activity of these neurons. We are testing if deficits in GABAergic inhibition impinging on hypothalamic PVN neurons results in dysregulation of the HPA axis that, in turn, leads to mood disorders associated with aging.
Figure 2. Subsets of aged animals exhibit anxiety-like and depression-like behavior. Subsets of 18 month old mice exhibit anxiety-like behavior in the open field test (a) and depression-like behavior in the Porsolt forced swim test (c). The distribution of time spent in the center squares in the open field test (b) and the distribution of the total time spent immobile during the Porsolt forced swim test (d) demonstrate that there are a population of aged mice exhibiting anxiety-like behavior and depression-like behavior, respectively.
GABAergic Control of the HPA Axis in the Co-morbidity of Depression and Epilepsy
We are testing the hypothesis that GABAergic dysregulation of the HPA axis plays a role in the co-morbidity of depression and epilepsy and, thereby, uncover essential information regarding the principal mechanisms underlying the pathophysiology and potential treatments of these disorders. We recently discovered deficits in δ subunit-mediated GABAergic inhibition associated with both depression and epilepsy, and that this deficit results in increased levels of the stress hormone corticosterone. Since major depression is associated with hyperactivity of the HPA axis, and seizures activate the HPA axis, we hypothesize that deficits in GABAergic control of the HPA axis contributes to depression in epilepsy.
GABAergic Control of the HPA Axis in Seizure Susceptibility
We generated mice in which the K/Cl co-transporter, KCC2, is knocked out only in CRH neurons, which is sufficient to decrease GABAergic control of these neurons and result in hyperexcitability of the HPA axis. We are utilizing this model to investigate the role of GABAergic control of the HPA axis in seizure susceptibility.
Figure 3. Increased seizure susceptibility associated with hyperexcitability of the HPA axis. We generated a mouse model deficient in KCC2 specifically in CRH neurons (KCC2/CRH) which induces hyperexcitability of the HPA axis. Representative EEG traces from control and KC2/CRH mice demonstrate that hyperexcitability of the HPA axis in these animals is associated with an increase in seizure susceptibility in response to 20mg/kg kainic acid.
Learn more about the Maguire Lab