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ABSTRACT: The hypothalamic-pituitary-adrenal (HPA) axis, which mediates the body's response to stress, is largely under GABAergic control. Here we demonstrate that corticotropin-releasing hormone (CRH) neurons are modulated by the stress-derived neurosteroid, tetrahydrodeoxycorticosterone (THDOC), acting on δ subunit-containing GABA(A) receptors (GABA(A)Rs). Under normal conditions, THDOC potentiates the inhibitory effects of GABA on CRH neurons, decreasing the activity of the HPA axis. Counterintuitively, following stress, THDOC activates the HPA axis due to dephosphorylation of KCC2 residue Ser940, resulting in a collapse of the chloride gradient and excitatory GABAergic transmission. The effects of THDOC on CRH neurons are mediated by actions on GABA(A)R δ subunit-containing receptors since these effects are abolished in Gabrd(-/-) mice under both control and stress conditions. Interestingly, blocking neurosteroidogenesis with finasteride is sufficient to block the stress-induced elevations in corticosterone and prevent stress-induced anxiety-like behaviors in mice. These data demonstrate that positive feedback of neurosteroids onto CRH neurons is required to mount the physiological response to stress. Further, GABA(A)R δ subunit-containing receptors and phosphorylation of KCC2 residue Ser940 may be novel targets for control of the stress response, which has therapeutic potential for numerous disorders associated with hyperexcitability of the HPA axis, including Cushing's syndrome, epilepsy, and major depression.
Journal of Neuroscience 12/2011; 31(50):18198-210. · 7.11 Impact Factor
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ABSTRACT: Inhibitory neurotransmission is primarily governed by γ-aminobutyric acid (GABA) type A receptors (GABAARs). GABAARs are heteropentameric ligand-gated channels formed by the combination of 19 possible subunits. GABAAR subunits are subject to multiple types of regulation, impacting the localization, properties, and function of assembled receptors. GABAARs mediate both phasic (synaptic) and tonic (extrasynaptic) inhibition. While the regulatory mechanisms governing synaptic receptors have begun to be defined, little is known about the regulation of extrasynaptic receptors. We examine the contributions of GABAARs to the pathogenesis of neurodevelopmental disorders, schizophrenia, depression, epilepsy, and stroke, with particular focus on extrasynaptic GABAARs. We suggest that extrasynaptic GABAARs are attractive targets for the treatment of these disorders, and that research should be focused on delineating the mechanisms that regulate extrasynaptic GABAARs, promoting new therapeutic approaches.
Current opinion in neurobiology 10/2011; 22(3):552-8. · 7.21 Impact Factor
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ABSTRACT: The Rbfox family of RNA binding proteins regulates alternative splicing of many important neuronal transcripts, but its role in neuronal physiology is not clear. We show here that central nervous system-specific deletion of the gene encoding Rbfox1 results in heightened susceptibility to spontaneous and kainic acid-induced seizures. Electrophysiological recording revealed a corresponding increase in neuronal excitability in the dentate gyrus of the knockout mice. Whole-transcriptome analyses identified multiple splicing changes in the Rbfox1(-/-) brain with few changes in overall transcript abundance. These splicing changes alter proteins that mediate synaptic transmission and membrane excitation. Thus, Rbfox1 directs a genetic program required in the prevention of neuronal hyperexcitation and seizures. The Rbfox1 knockout mice provide a new model to study the post-transcriptional regulation of synaptic function.
Nature Genetics 05/2011; 43(7):706-11. · 35.53 Impact Factor
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ABSTRACT: Stress-derived steroid hormones regulate the expression and function of GABA(A) receptors (GABA(A)Rs). Changes in GABA(A)R subunit expression have been demonstrated under conditions of altered steroid hormone levels, such as stress, as well as following exogenous steroid hormone administration. In addition to the effects of stress-derived steroid hormones on GABA(A)R subunit expression, stress hormones can also be metabolized to neuroactive derivatives which can alter the function of GABA(A)Rs. Neurosteroids allosterically modulate GABA(A)Rs at concentrations comparable to those during stress. In addition to the actions of stress-derived steroid hormones on GABA(A)Rs, GABA(A)Rs reciprocally regulate the production of stress hormones. The stress response is mediated by the hypothalamic-pituitary-adrenal (HPA) axis, the activity of which is governed by corticotropin releasing hormone (CRH) neurons. The activity of CRH neurons is largely controlled by robust GABAergic inhibition. Recently, it has been demonstrated that CRH neurons are regulated by neurosteroid-sensitive, GABA(A)R δ subunit-containing receptors representing a novel feedback mechanism onto the HPA axis. Further, it has been demonstrated that neurosteroidogenesis and neurosteroid actions on GABA(A)R δ subunit-containing receptors on CRH neurons are necessary to mount the physiological response to stress. Here we review the literature describing the effects of steroid hormones on GABA(A)Rs as well as the importance of GABA(A)Rs in regulating the production of steroid hormones. This review incorporates what we currently know about changes in GABA(A)Rs following stress and the role in HPA axis regulation.
Frontiers in Cellular Neuroscience 01/2011; 6:4. · 4.17 Impact Factor
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ABSTRACT: GABA is the principal inhibitory neurotransmitter in the CNS and acts via GABA(A) and GABA(B) receptors. Recently, a novel form of GABA(A) receptor-mediated inhibition, termed "tonic" inhibition, has been described. Whereas synaptic GABA(A) receptors underlie classical "phasic" GABA(A) receptor-mediated inhibition (inhibitory postsynaptic currents), tonic GABA(A) receptor-mediated inhibition results from the activation of extrasynaptic receptors by low concentrations of ambient GABA. Extrasynaptic GABA(A) receptors are composed of receptor subunits that convey biophysical properties ideally suited to the generation of persistent inhibition and are pharmacologically and functionally distinct from their synaptic counterparts. This mini-symposium review highlights ongoing work examining the properties of recombinant and native extrasynaptic GABA(A) receptors and their preferential targeting by endogenous and clinically relevant agents. In addition, it emphasizes the important role of extrasynaptic GABA(A) receptors in GABAergic inhibition throughout the CNS and identifies them as a major player in both physiological and pathophysiological processes.
Journal of Neuroscience 10/2009; 29(41):12757-63. · 7.11 Impact Factor
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ABSTRACT: Alterations in GABA(A) receptor (GABA(A)R) expression and function, similar to those we described previously during pregnancy in the mouse dentate gyrus, may also occur in other brain regions. Here we show, using immunohistochemical techniques, a decreased delta subunit-containing GABA(A)R (deltaGABA(A)R) expression in the dentate gyrus, hippocampal CA1 region, thalamus, and striatum but not in the cerebral cortex. In the face of the highly elevated neurosteroid levels during pregnancy, which can act on deltaGABA(A)Rs, it may be beneficial to decrease the number of neurosteroid-sensitive receptors to maintain a steady-state level of neuronal excitability throughout pregnancy. Consistent with this hypothesis, the synaptic input/output (I/O) relationship in the dentate gyrus molecular layer in response to lateral perforant path stimulation was shifted to the left in hippocampal slices from pregnant compared with virgin mice. The addition of allopregnanolone, at levels comparable with those found during pregnancy (100 nM), shifted the I/O curves in pregnant mice back to virgin levels. There was a decreased threshold to induce epileptiform local field potentials in slices from pregnant mice compared with virgin, but allopregnanolone reverted the threshold for inducing epileptiform activity to virgin levels. According to these data, neuronal excitability is increased in pregnant mice in the absence of allopregnanolone attributable to brain region-specific downregulation of deltaGABA(A)R expression. In brain regions, such as the cortex, that do not exhibit alterations in deltaGABA(A)R expression, there were no changes in the I/O relationship during pregnancy. Similarly, no changes in network excitability were detected in pregnant Gabrd(-/-) mice that lack deltaGABA(A)Rs, suggesting that changes in neuronal excitability during pregnancy are attributable to alterations in the expression of these receptors. Our findings indicate that alterations in deltaGABA(A)R expression during pregnancy result in brain region-specific increases in neuronal excitability that are restored by the high levels of allopregnanolone under normal conditions but under pathological conditions may result in neurological and psychiatric disorders associated with pregnancy and postpartum.
Journal of Neuroscience 08/2009; 29(30):9592-601. · 7.11 Impact Factor
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ABSTRACT: 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.
Psychoneuroendocrinology 08/2009; 34 Suppl 1:S84-90. · 5.81 Impact Factor
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ABSTRACT: Fluctuating neurosteroid levels over the ovarian cycle modulate neuronal excitability through effects on GABA(A) receptors (GABA(A)Rs). The large increase in progesterone-derived neurosteroids during pregnancy and their precipitous decline at parturition may have considerable effects on GABA(A)Rs during pregnancy and postpartum. Here we show a significant decrease in tonic and phasic inhibitions in pregnant mice, mediated by a downregulation of GABA(A)R delta and gamma2 subunits, respectively, which rebounds immediately postpartum. Mice which do not exhibit GABA(A)R delta subunit regulation throughout pregnancy (Gabrd(+/-) and Gabrd(-/-)) exhibit depression-like and abnormal maternal behaviors, resulting in reduced pup survival. These abnormal postpartum behaviors were ameliorated in Gabrd(+/-) mice by a GABA(A)R delta-subunit-selective agonist, THIP. We suggest that Gabrd(+/-) and Gabrd(-/-) mice constitute a mouse model of postpartum depression that may be useful for evaluating potential therapeutic interventions.
Neuron 08/2008; 59(2):207-13. · 14.74 Impact Factor
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ABSTRACT: Recently, we demonstrated cyclic alterations in GABA(A) receptor (GABA(A)R) subunit composition over the ovarian cycle correlated with fluctuations in progesterone levels. However, it remains unclear whether this physiological regulation of GABA(A)Rs is directly mediated by hormones. Here, we show that both ovarian and stress hormones are capable of reorganizing GABA(A)Rs by actions through neurosteroid metabolites. The cyclic alterations in GABA(A)Rs demonstrated in female mice can be mimicked with exogenous progesterone treatment in males or in ovariectomized females. Progesterone (5 mg/kg, twice daily) upregulates the expression of GABA(A)R delta subunits and enhances the tonic inhibition mediated by these receptors in dentate gyrus granule cells (DGGCs). These changes in males as well as ovarian cycle-induced changes in females can be blocked by finasteride, an antagonist of neurosteroid synthesis from progesterone. The altered GABA(A)R expression is unaffected by the progesterone receptor antagonist RU486 [mifepristone (11beta-[p-(dimethylamino)phenyl]-17beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)], suggesting that neurosteroid synthesis and not progesterone receptor activation underlies the hormone-mediated effects on GABA(A)R expression. Neurosteroids can alter GABA(A)R expression on a rapid timescale, because GABA(A)R upregulation can be induced in brain slices maintained in vitro after a short (30 min) treatment with the neurosteroid 3alpha,5alpha-tetrahydrodeoxycorticosterone (THDOC) (100 nM). Consistent with these rapid alterations, acute stress, a condition known to quickly raise THDOC levels, within 30 min induces upregulation of GABA(A)R delta subunit expression and increase tonic inhibition in DGGCs. These results reveal that several physiological conditions characterized by elevations in neurosteroid levels induce a reorganization of GABA(A)Rs through the action of neurosteroids.
Journal of Neuroscience 03/2007; 27(9):2155-62. · 7.11 Impact Factor
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ABSTRACT: Selected mutations in the human alpha4 or beta2 neuronal nicotinic acetylcholine receptor subunit genes cosegregate with a partial epilepsy syndrome known as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To examine possible mechanisms underlying this inherited epilepsy, we engineered two ADNFLE mutations (Chrna4(S252F) and Chrna4(+L264)) in mice. Heterozygous ADNFLE mutant mice show persistent, abnormal cortical electroencephalograms with prominent delta and theta frequencies, exhibit frequent spontaneous seizures, and show an increased sensitivity to the proconvulsant action of nicotine. Relative to WT, electrophysiological recordings from ADNFLE mouse layer II/III cortical pyramidal cells reveal a >20-fold increase in nicotine-evoked inhibitory postsynaptic currents with no effect on excitatory postsynaptic currents. i.p. injection of a subthreshold dose of picrotoxin, a use-dependent gamma-aminobutyric acid receptor antagonist, reduces cortical electroencephalogram delta power and transiently inhibits spontaneous seizure activity in ADNFLE mutant mice. Our studies suggest that the mechanism underlying ADNFLE seizures may involve inhibitory synchronization of cortical networks via activation of mutant alpha4-containing nicotinic acetylcholine receptors located on the presynaptic terminals and somatodendritic compartments of cortical GABAergic interneurons.
Proceedings of the National Academy of Sciences 01/2007; 103(50):19152-7. · 9.68 Impact Factor
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ABSTRACT: 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.
Psychoneuroendocrinology.
