Jamie Maguire

Tufts University, Georgia, United States

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Publications (20)152.85 Total impact

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    ABSTRACT: Neurosteroids are synthesized within the brain and act as endogenous anxiolytic, anticonvulsant, hypnotic, and sedative agents, actions that are principally mediated via their ability to potentiate phasic and tonic inhibitory neurotransmission mediated by γ-aminobutyric acid type A receptors (GABAARs). Although neurosteroids are accepted allosteric modulators of GABAARs, here we reveal they exert sustained effects on GABAergic inhibition by selectively enhancing the trafficking of GABAARs that mediate tonic inhibition. We demonstrate that neurosteroids potentiate the protein kinase C-dependent phosphorylation of S443 within α4 subunits, a component of GABAAR subtypes that mediate tonic inhibition in many brain regions. This process enhances insertion of α4 subunit-containing GABAAR subtypes into the membrane, resulting in a selective and sustained elevation in the efficacy of tonic inhibition. Therefore, the ability of neurosteroids to modulate the phosphorylation and membrane insertion of α4 subunit-containing GABAARs may underlie the profound effects these endogenous signaling molecules have on neuronal excitability and behavior.
    Proceedings of the National Academy of Sciences 04/2014; · 9.74 Impact Factor
  • Jamie Maguire
    BioEssays 04/2014; · 5.42 Impact Factor
  • Georgina Mackenzie, Jamie Maguire
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    ABSTRACT: Neuroactive derivatives of steroid hormones, neurosteroids, can act on GABAA receptors (GABAARs) to potentiate the effects of GABA on these receptors. Neurosteroids become elevated to physiologically relevant levels under conditions characterized by increased steroid hormones. There is considerable evidence for plasticity of GABAARs associated with altered levels of neurosteroids which may counteract the fluctuations in the levels of these allosteric modulators. The objective of this review is to summarize the current literature on GABAAR plasticity under conditions characterized by alterations in neurosteroid levels, such as over the estrous cycle, during puberty, and throughout pregnancy and the postpartum period. The expression of specific GABAAR subunits is altered over the estrous cycle, at puberty, and throughout pregnancy and the postpartum period. Inability to regulate δ subunit-containing GABAARs throughout pregnancy and the postpartum period is associated with depression-like behavior restricted to the postpartum period. GABAAR plasticity associated with alterations in neurosteroid levels represents a homeostatic compensatory mechanism to maintain an ideal level of inhibition to offset the potentiating effects of neurosteroids on GABAergic inhibition. Failure to properly regulate GABAARs under conditions of altered neurosteroid levels may increase vulnerability to mood disorders, such as premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and postpartum depression.
    Psychopharmacology 01/2014; · 4.06 Impact Factor
  • Vallent Lee, Jhimly Sarkar, Jamie Maguire
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    ABSTRACT: The hypothalamic–pituitary–adrenal (HPA) axis is under tight regulation by strong GABAergic inhibition onto corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus. CRH neurons receive two forms of GABAergic inhibition, phasic and tonic, but the specific roles of these two types of signaling have not yet been studied in this cell type. Our lab recently demonstrated a role for the GABAAR δ subunit in the tonic GABAergic regulation of CRH neurons. Using a floxed Gabrd mouse model established in our laboratory, we generated mice in which the GABAAR δ subunit is selectively removed from CRH neurons (Gabrd/Crh mice), resulting in a loss of tonic GABAergic inhibition in these neurons. Interestingly, the loss of this tonic GABAergic constraint did not significantly alter basal levels of corticosterone (CORT). However, the loss of the GABAAR δ subunit in CRH neurons blunted the CORT response to stress, likely due to the loss of the disinhibitory effect of GABA following acute stress. This blunting of HPA axis reactivity was associated with a decrease in depression-like and anxiety-like behaviors. Exogenous CORT was sufficient to increase anxiety-like and depression-like behaviors in Gabrd/Crh mice. Together, these results show the importance of the GABAAR δ subunit in the regulation of CRH neurons, and thus the HPA axis, and demonstrate that dysregulation of CRH neurons alters stress-related behaviors.
    Psychoneuroendocrinology 01/2014; 41:75–88. · 5.14 Impact Factor
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    Vallent Lee, Jamie Maguire
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    ABSTRACT: The diversity of GABAA receptor (GABAAR) subunits and the numerous configurations during subunit assembly give rise to a variety of receptors with different functional properties. This heterogeneity results in variations in GABAergic conductances across numerous brain regions and cell types. Phasic inhibition is mediated by synaptically-localized receptors with a low affinity for GABA and results in a transient, rapidly desensitizing GABAergic conductance; whereas, tonic inhibition is mediated by extrasynaptic receptors with a high affinity for GABA and results in a persistent GABAergic conductance. The specific functions of tonic versus phasic GABAergic inhibition in different cell types and the impact on specific neural circuits are only beginning to be unraveled. Here we review the diversity in the magnitude of tonic GABAergic inhibition in various brain regions and cell types, and highlight the impact on neuronal excitability in different neuronal circuits. Further, we discuss the relevance of tonic inhibition in various physiological and pathological contexts as well as the potential of targeting these receptor subtypes for treatment of diseases, such as epilepsy.
    Frontiers in Neural Circuits 01/2014; 8:3. · 3.33 Impact Factor
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    ABSTRACT: Stress is the most commonly reported precipitating factor for seizures. The proconvulsant actions of stress hormones are thought to mediate the effects of stress on seizure susceptibility. Interestingly, epileptic patients have increased basal levels of stress hormones, including corticotropin-releasing hormone (CRH) and corticosterone, which are further increased following seizures. Given the proconvulsant actions of stress hormones, we proposed that seizure-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to future seizure susceptibility. Consistent with this hypothesis, our data demonstrate that pharmacological induction of seizures in mice with kainic acid or pilocarpine increases circulating levels of the stress hormone, corticosterone, and exogenous corticosterone administration is sufficient to increase seizure susceptibility. However, the mechanism(s) whereby seizures activate the HPA axis remain unknown. Here we demonstrate that seizure-induced activation of the HPA axis involves compromised GABAergic control of CRH neurons, which govern HPA axis function. Following seizure activity, there is a collapse of the chloride gradient due to changes in NKCC1 and KCC2 expression, resulting in reduced amplitude of sIPSPs and even depolarizing effects of GABA on CRH neurons. Seizure-induced activation of the HPA axis results in future seizure susceptibility which can be blocked by treatment with an NKCC1 inhibitor, bumetanide, or blocking the CRH signaling with Antalarmin. These data suggest that compromised GABAergic control of CRH neurons following an initial seizure event may cause hyperexcitability of the HPA axis and increase future seizure susceptibility.
    Epilepsy research 10/2013; · 2.48 Impact Factor
  • Vallent Lee, Jamie Maguire
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    ABSTRACT: Tonic inhibition is thought to dampen the excitability of principal neurons; however, little is known about the role of tonic GABAergic inhibition in interneurons and the impact on principal neuron excitability. In many brain regions, tonic GABAergic inhibition is mediated by extrasynaptic, δ subunit-containing GABAA receptors (GABAARs). Here we demonstrate the importance of GABAAR δ subunit-mediated tonic inhibition in interneurons. Selective elimination of the GABAAR δ subunit from interneurons was achieved by crossing a novel floxed Gabrd mouse model with GAD65-Cre mice (Gabrd/Gad mice). Deficits in GABAAR δ subunit expression in GAD65-positive neurons result in a decrease in tonic GABAergic inhibition and increased excitability of both molecular layer (ML) and stratum radiatum (SR) interneurons. Disinhibition of interneurons results in robust alterations in the neuronal excitability of principal neurons and decreased seizure susceptibility. Gabrd/Gad mice have enhanced tonic and phasic GABAergic inhibition in both CA1 pyramidal neurons and dentate gyrus granule cells (DGGCs). Consistent with alterations in hippocampal excitability, CA1 pyramidal neurons and DGGCs from Gabrd/Gad mice exhibit a shift in the input-output relationship towards decreased excitability compared to Cre(-/-) littermates. Furthermore, seizure susceptibility, in response to 20 mg/kg kainic acid, is significantly decreased in Gabrd/Gad mice compared to Cre(-/-) controls. These data demonstrate a critical role for GABAAR δ subunit-mediated tonic GABAergic inhibition of interneurons on principal neuronal excitability and seizure susceptibility.
    Journal of Neurophysiology 09/2013; · 3.30 Impact Factor
  • Georgina Mackenzie, jamie maguire
    Biomolecular concepts 01/2013; 4(1):29-42.
  • Tarek Z. Deeb, Jamie Maguire, Stephen J. Moss
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    ABSTRACT: Benzodiazepines have been used for decades as first-line treatment for status epilepticus (SE). For reasons that are not fully understood, the efficacy of benzodiazepines decreases with increasing duration of seizure activity. This often forces clinicians to resort to more drastic second- and third-line treatments that are not always successful. The antiseizure properties of benzodiazepines are mediated by γ-aminobutyric acid type A (GABAA) receptors. Decades of research have focused on the failure of GABAergic inhibition after seizure onset as the likely cause of the development benzodiazepine resistance during SE. However, the details of the deficits in GABAA signaling are still largely unknown. Therefore, it is necessary to improve our understanding of the mechanisms of benzodiazepine resistance so that more effective strategies can be formulated. In this review we discuss evidence supporting the role of altered GABAA receptor function as the major underlying cause of benzodiazepine-resistant SE in both humans and animal models. We specifically address the prevailing hypothesis, which is based on changes in the number and subtypes of GABAA receptors, as well as the potential influence of perturbed chloride homeostasis in the mature brain.
    Epilepsia 12/2012; 53(s9). · 3.96 Impact Factor
  • Jamie Maguire, Jay A Salpekar
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    ABSTRACT: Epilepsy is a heterogeneous condition with varying etiologies including genetics, infection, trauma, vascular, neoplasms, and toxic exposures. The overlap of psychiatric comorbidity adds to the challenge of optimal treatment for people with epilepsy. Seizure episodes themselves may have varying triggers; however, for decades, stress has been commonly and consistently suspected to be a trigger for seizure events. This paper explores the relationship between stress and seizures and reviews clinical data as well as animal studies that increasingly corroborate the impact of stress hormones on neuronal excitability and seizure susceptibility. The basis for enthusiasm for targeting glucocorticoid receptors for the treatment of epilepsy and the mixed results of such treatment efforts are reviewed. In addition, this paper will highlight recent findings identifying a regulatory pathway controlling the body's physiological response to stress which represents a novel therapeutic target for modulation of the hypothalamic-pituitary-adrenal (HPA) axis. Thus, the HPA axis may have important clinical implications for seizure control and imply use of anticonvulsants that influence this neuronal pathway. This article is part of a Special Issue entitled "Translational Epilepsy Research".
    Epilepsy & Behavior 11/2012; · 1.84 Impact Factor
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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. · 6.91 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. · 35.21 Impact Factor
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    Istvan Mody, Jamie Maguire
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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. · 4.47 Impact Factor
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    Jamie Maguire, Istvan Mody
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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. · 5.14 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. · 6.91 Impact Factor
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    Jamie Maguire, Istvan Mody
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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. · 15.77 Impact Factor
  • Jamie Maguire, Istvan Mody
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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. · 6.91 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. · 9.81 Impact Factor
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    ABSTRACT: Disturbances of neuronal excitability changes during the ovarian cycle may elevate seizure frequency in women with catamenial epilepsy and enhance anxiety in premenstrual dysphoric disorder (PMDD). The mechanisms underlying these changes are unknown, but they could result from the effects of fluctuations in progesterone-derived neurosteroids on the brain. Neurosteroids and some anxiolytics share an important site of action: tonic inhibition mediated by delta subunit-containing GABA(A) receptors (deltaGABA(A)Rs). Here we demonstrate periodic alterations in specific GABA(A)R subunits during the estrous cycle in mice, causing cyclic changes of tonic inhibition in hippocampal neurons. In late diestrus (high-progesterone phase), enhanced expression of deltaGABA(A)Rs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling of deltaGABA(A)Rs by antisense RNA treatment or gene knockout prevents the lowering of excitability during diestrus. Our findings are consistent with possible deficiencies in regulatory mechanisms controlling normal cycling of deltaGABA(A)Rs in individuals with catamenial epilepsy or PMDD.
    Nature Neuroscience 07/2005; 8(6):797-804. · 15.25 Impact Factor

Publication Stats

701 Citations
152.85 Total Impact Points

Institutions

  • 2011–2014
    • Tufts University
      • Department of Neuroscience
      Georgia, United States
  • 2009
    • University of Southern California
      Los Angeles, California, United States
  • 2005–2009
    • University of California, Los Angeles
      • Department of Neurology
      Los Angeles, CA, United States